Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors

ABSTRACT

The disclosure relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula: 
                         
where R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , X 1 , X 2 , X 3 , n, and m are described herein.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. provisionalapplication No. 62/112,540, filed Feb. 5, 2015, the entire contents ofwhich are incorporated herein by reference in its entirety.

FIELD OF DISCLOSURE

The present disclosure is directed to inhibitors of ubiquitin-specificprotease 7 (USP7) useful in the treatment of diseases or disordersassociated with USP7 enzymes. Specifically, the disclosure is concernedwith compounds and compositions inhibiting USP7, methods of treatingdiseases or disorders associated with USP7, and methods of synthesis ofthese compounds.

BACKGROUND OF THE DISCLOSURE

Ubiquitination is a post translational modification initially identifiedas a crucial component of proteasomal degradation in the ubiquitinproteasome system (UPS). Chains of Ubiquitin (Ub(s)), an 8.5 kDa highlyconserved protein, are covalently attached to substrates to be degradedin the proteasome. (Finley D. “Recognition and processing ofubiquitin-protein conjugates by the proteasome.” Annual review ofbiochemistry 78:477-513, (2009)) The molecular mechanisms by which theUPS acts are also varied, with different chain linkages ofubiquitination controlling protein turnover, enzymatic activity,subcellular localization, and protein-protein interactions of substrateproteins. (Komander D., et. al. “The emerging complexity of proteinubiquitination,” Biochem. Soc. Trans. 37(Pt 5):937-53 (2009))

Ubiquitin-specific protease 7 (USP7) is a Ubiquitin Specific Protease(USP) family deubiquitinase (DUB) that was originally identified as anenzyme that interacted with virally-encoded proteins of the Herpessimplex virus and later the Epstein-Barr virus. (Everett R. D., MeredithM., Orr A., Cross A, Kathoria M., Parkinson J. “A novelubiquitin-specific protease is dynamically associated with the PMLnuclear domain and binds to a herpes virus regulatory protein,” EMBO J.16(7):1519-30 (1997); Holowaty M. N., Zeghouf M., Wu H., et al. “Proteinprofiling with Epstein-Barr nuclear antigen-1 reveals an interactionwith the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7,”J. Biol. Chem. 278(32):29987-94 (2003)) Ubiquitin Specific Proteases(USPs) specifically cleave the isopeptide bond at the carboxy terminusof ubiquitin. In contrast to other DUB classes, which are thought togenerally regulate ubiquitin homeostasis or to be involved inpre-processing of linear ubiquitin chains, USPs remove ubiquitin fromspecific targets. Given this substrate specificity combined with thenumerous roles ubiquitination has in the cell, USPs are importantregulators of a multitude of pathways, ranging from preventing theproteolysis of ubquitinated substrates, to controlling their nuclearlocalization.

USP7 deubiquitinates a variety of cellular targets involved in differentprocesses related to cancer and metastasis, neurodegenerative diseases,immunological disorders, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, and bacterial infections and diseases.

For example, USP7 has been shown to stabilize DNMT1, a DNAmethyltransferase that maintain epigenetic silencing, to maintain highersteady state-levels of Claspin, a protein involved in ataxiatelangiectasia and Rad3-related (ATR) phosphorylation of Chk1, and toregulate Tip60 protein levels, a histone acetyltransferase andtranscriptional coregulator involved in adipogenesis. (Zhanwen du, SongJ., Wang Y., et al. “DNMT1 stability is regulated by proteinscoordinating deubiquitination and acetylation-driven ubiquitination,”Science Signaling 3(146) (2010); Faustrup H., Bekker-Jensen S., BartekJ., Lukas J., Mail N., Mailand N. “USP7 counteracts SCFbetaTrCP- but notAPCCdh1-mediated proteolysis of Claspin,” The Journal of cell biology184(1):13-9 (2009); Gao Y., Koppen A., Rakhsh M., et al. “Earlyadipogenesis is regulated through USP7-mediated deubiquitination of thehistone acetyltransferase TIP60,” Nature Communications 4:2656 (2013)

In addition to regulating the protein stability of poly-ubiquitinatedtargets, USP7 also acts to control the subcellular localization ofproteins. Mono-ubiquitination of PTEN has been shown to effect itscytoplasmic/nuclear partitioning, where nuclear localization of PTEN isimportant for its tumor suppression activity. (Trotman L. C., Wang X.,Alimonti A., et al. “Ubiquitination regulates PTEN nuclear import andtumor suppression,” Cell 128(1):141-56 (2007); Song M. S., Salmena L.,Carracedo A., et al. “The deubiquitinylation and localization of PTENare regulated by a HAUSP-PML network,” Nature 455(7214):813-7 (2008))USP7 has also been shown to bind and deubiquitinate FOXO4, a member ofthe FOXO subfamily of transcription factors involved in a variety ofcell processes including metabolism, cell cycle regulation apoptosis,and response to oxidative stress, decreasing its nuclear localizationand transcriptional activity. (van der Horst A., van der Horst O., deVries-Smits A. M. M., et al. “FOXO4 transcriptional activity isregulated by monoubiquitination and USP7/HAUSP,” Nat. Cell Biol.8(10):1064-73 (2006))

Cellular targets of USP7 also include the tumor suppressor p53 and itsmajor E3 ligase, MDM2, stabilizing p53 via the degradation of MDM2. (LiM., Chen D., Shiloh A., et al. “Deubiquitination of p53 by HAUSP is animportant pathway for p53 stabilization,” Nature 416(6881):648-53(2002); Li M., Brooks C. L., Kon N., Gu W. “A dynamic role of HAUSP inthe p53-Mdm2 pathway,” Mol. Cell. 13(6):879-86 (2004)) Structuralstudies have also shown that the EBNA1 protein encoded by theEpstein-Barr virus interacts at the same binding surface as USP7 on p53,preventing USP7 endogenous cellular activity while recruiting USP7 toviral promoters in order to activate latent viral gene expression.(Saridakis V., et al. “Structure of the p53 binding domain of HAUSP/USP7bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediatedimmortalization,” Mol. Cell. 18(1):25-36 (2005); Sarkari F.,Sanchez-Alcaraz T., Wang S., Holowaty M. N., Sheng Y., Frappier L.“EBNA1-mediated recruitment of a histone H2B deubiquitylating complex tothe Epstein-Barr virus latent origin of DNA replication,” PLoS pathogens5(10) (2009); Sheng Y., et al. “Molecular recognition of p53 and MDM2 byUSP7/HAUSP,” Nat. Struct. Mol. Biol. 13(3):285-91 (2006)) Similarly, thegene product of TSPYL5, a gene frequently amplified in breast cancer andassociated with poor clinical outcome, alters the ubiquitination statusof p53 via its interaction with USP7. (Epping M. T., et al. “TSPYL5suppresses p53 levels and function by physical interaction with USP7,”Nat. Cell Biol. 13(1):102-8 (2011))

Inhibition of USP7 with small molecule inhibitors therefore has thepotential to be a treatment for cancers and other disorders. For thisreason, there remains a considerable need for novel and potent smallmolecule inhibitors of USP7.

SUMMARY OF THE DISCLOSURE

A first aspect of the disclosure relates to compounds of Formula (I):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

X₂ is S or NR₆;

X₃ is N or CR₇, wherein, one of X₂ or X₃ is N;

R₁ is H, OH, SH, NH₂, or F;

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₈; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₁₈; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₁₈;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₁₈;

R₄ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₂;

R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, or CN;

R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆)haloalkyl;

R₇ is H, D, (C₁-C₆) alkyl, halogen, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₄;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₄ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, —OH, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₅;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

Another aspect of the disclosure relates to a method of treating adisease or disorder associated with modulation of USP7. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of USP7 an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the disclosure is directed to a method of inhibitingUSP7. The method involves administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the disclosure relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the disclosure relates to a method of treating aneurodegenerative disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the disclosure relates to a method of treating a viralinfection or disease. The method comprises administering to a patient inneed thereof an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the disclosure relates to a method of treating aninflammatory disease or condition. The method comprises administering toa patient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the disclosure relates to a method of inducing cellcycle arrest, apoptosis in tumor cells and/or enhanced tumor-specificT-cell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof and a pharmaceutically acceptable carrier. The pharmaceuticalacceptable carrier may further include an excipient, diluent, orsurfactant.

Another aspect of the present disclosure relates to a compound ofFormula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in the manufactureof a medicament for treating a disease associated with inhibiting USP7.

Another aspect of the present disclosure relates to the use of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment ofa disease associated with inhibiting USP7.

The present disclosure further provides methods of treating a disease ordisorder associated with modulation of USP7 including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

The present disclosure provides inhibitors of USP7 that are therapeuticagents in the treatment of diseases such as cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present disclosure further provides compounds and compositions withan improved efficacy and safety profile relative to known USP7inhibitors. The present disclosure also provides agents with novelmechanisms of action toward USP7 enzymes in the treatment of varioustypes of diseases including cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases. Ultimately thepresent disclosure provides the medical community with a novelpharmacological strategy for the treatment of diseases and disordersassociated with USP7 enzymes.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure relates to compounds and compositions that arecapable of inhibiting the activity USP7. The disclosure features methodsof treating, preventing or ameliorating a disease or disorder in whichUSP7 plays a role by administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. The methods of the present disclosurecan be used in the treatment of a variety of USP7 dependent diseases anddisorders by inhibiting the activity of USP7 enzymes. Inhibition of USP7provides a novel approach to the treatment, prevention, or ameliorationof diseases including, but not limited to, cancer and metastasis,neurodegenerative diseases, immunological disorders, osteoporosis,arthritis inflammatory disorders, cardiovascular diseases, ischemicdiseases, viral infections and diseases, and bacterial infections anddiseases.

In a first aspect of the disclosure, the compounds of Formula (I) aredescribed:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein R₁, R₂, R₃, R₄, R₅,R_(5′), X₁, X₂, X₃, m, and n are as described herein above.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (e.g., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (e.g., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH₂CN,—O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl,—C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, —NH((C₁-C₆) alkyl),—N((C₁-C₆) alkyl)₂, —NHC(O)(C₁-C₆) alkyl, —C(O)NH(C₁-C₆) alkyl,—S(O)₂(C₁-C₆) alkyl, —S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂.The substituents can themselves be optionally substituted. “Optionallysubstituted” as used herein also refers to substituted or unsubstitutedwhose meaning is described below.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, —O—(C₂-C₆) alkenyl,—O—(C₂-C₆) alkynyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂,—OC(O)(C₁-C₆) alkyl, —C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, NH₂,NH((C₁-C₆) alkyl), N((C₁-C₆) alkyl)₂, —S(O)₂—(C₁-C₆) alkyl,—S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include, but are not limited to,phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, andthe like.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2, 1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl,benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings thearyl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a (C₁-C₆) alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain,e.g., —O(alkyl). Examples of alkoxy groups include, without limitation,methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. Examples ofalkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl,pentenyl, or hexenyl. An alkenyl group can be unsubstituted orsubstituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynylgroup can be unsubstituted or substituted.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical.Any of the above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. As herein defined,alkylene may also be a C₁-C₆ alkylene. An alkylene may further be aC₁-C₄ alkylene. Typical alkylene groups include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Cycloalkyl” or “carbocyclyl” means monocyclic or polycyclic saturatedcarbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof.A C₃-C₈ cycloalkyl is a cycloalkyl group containing between 3 and 8carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged(e.g., norbornane).

“Heterocyclyl” or “heterocycloalkyl” monocyclic or polycyclic ringscontaining carbon and heteroatoms taken from oxygen, nitrogen, or sulfurand wherein there is not delocalized π electrons (aromaticity) sharedamong the ring carbon or heteroatoms. The heterocycloalkyl ringstructure may be substituted by one or more substituents. Thesubstituents can themselves be optionally substituted. Examples ofheterocyclyl rings include, but are not limited to, oxetanyl,azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl,thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl,and homotropanyl.

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, e.g., C≡N.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom (e.g., NH₂).

The term “alkylamino” as used herein refers to an amino or NH₂ groupwhere one of the hydrogens has been replaced with an alkyl group, asdefined herein above, e.g., —NH(alkyl). Examples of alkylamino groupsinclude, but are not limited to, methylamino (e.g., —NH(CH₃)),ethylamino, propylamino, iso-propylamino, n-butylamino, sec-butylamino,tert-butylamino, etc.

The term “dialkylamino” as used herein refers to an amino or NH₂ groupwhere both of the hydrogens have been replaced with alkyl groups, asdefined herein above, e.g., —N(alkyl)₂. The alkyl groups on the aminogroup can be the same or different alkyl groups. Example of dialkylaminogroups include, but are not limited to, dimethylamino (e.g., —N(CH₃)₂),diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino,di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino,methyl(butylamino), etc.

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ringsystems with both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A (C₃-C₁₂)spirocycloalkyl is a spirocycle containing between 3 and 12 carbonatoms. One or more of the carbon atoms can be substituted with aheteroatom.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood tomean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the disclosuremay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumerate, fiunarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,mucate, napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

The present disclosure relates to compounds or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, capable of inhibiting USP7, which are useful for thetreatment of diseases and disorders associated with modulation of a USP7enzyme. The disclosure further relates to compounds, or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, which are useful for inhibiting USP7.

In one embodiment, the compounds of Formula (I) have the structure ofFormula (Ia):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₁ is H, OH, SH, NH₂, or F;

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₈; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₁₈; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₁₈;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₁₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, or CN;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ib):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₁ is H, OH, SH, NH₂, or F;

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₈; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₁₈; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₁₈;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₁₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, or CN;

R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆)haloalkyl;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ic):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₁ is H, OH, SH, NH₂, or F;

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₈; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₁₈; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₁₈;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₁₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, or CN;

R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆)haloalkyl;

R₇ is H, D, (C₁-C₆) alkyl, halogen, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₄;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)NR₁₉R₂₀, —NR₁₉S(O)_(q)R₂₀,—(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀, —NR₁₉C(O)C(O)R₂₀,—NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, or—OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₄ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, —OH, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₅;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Id):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₈; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₁₈; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₁₈;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₁₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ie):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₈; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₁₈; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₁₈;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₁₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆)haloalkyl;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (If):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₈; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₁₈; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₁₈; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₁₈;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₁₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆)haloalkyl;

R₇ is H, D, (C₁-C₆) alkyl, halogen, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₄;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₄ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, —OH, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₅;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ig):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ih):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆)haloalkyl;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ii):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈;

R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₂;

R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆)haloalkyl;

R₇ is H, D, (C₁-C₆) alkyl, halogen, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₄;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀,—NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀,—NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, —C(O)R₂₁,—C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₄;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆;

each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆,—NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₃; or

two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₃; or two R₁₂ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₁₃; or two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃; or two R₁₂ togetherwhen on adjacent atoms form an heteroaryl ring optionally substitutedwith one or more R₁₃;

each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₇;

each R₁₄ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, —OH, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₅;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₇;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₃;

each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN; and

q is independently at each occurrence 0, 1, or 2.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is S. In yet another embodiment, X₁ is S(O).

In some embodiments of the Formulae above, X₂ is S. In anotherembodiment, X₂ is NR₆.

In some embodiments of the Formulae above, X₃ is N. In anotherembodiment, X₃ is CR₇.

In some embodiments of the Formulae above, R₁ is H, OH, SH, NH₂, or F.In another embodiment, R₁ is H, OH, or F. In yet another embodiment, R₁is OH, or F. In another embodiment, R₁ is OH.

In some embodiments of the Formulae above, R₂ is (C₁-C₆) alkyl, (C₆-C₁₄)aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl, or NR₁₀R₁₁,wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl areoptionally substituted with one or more R₈. In another embodiment, R₂ is(C₁-C₄) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₈. In yet another embodiment, R₂ is (C₁-C₄) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl, or NR₁₀R₁₁, whereinthe alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl areoptionally substituted with one to three R₈. In another embodiment, R₂is (C₁-C₄) alkyl, (C₆-C₁₄) aryl, heteroaryl, or NR₁₀R₁₁, wherein thealkyl, aryl, or heteroaryl are optionally substituted with one to threeR₈. In yet another embodiment, R₂ is (C₁-C₄) alkyl, (C₆-C₁₄) aryl, orNR₁₀R₁₁, wherein the alkyl and aryl are optionally substituted with oneto three R₈.

In some embodiments of the Formulae above, R₃ is selected from D,(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₈. Inanother embodiment, R₃ is selected from D or (C₁-C₆) alkyl, optionallysubstituted with one or more R₁₈. In yet another embodiment, R₃ isselected from D or (C₁-C₆) alkyl, optionally substituted with one tothree R₁₈. In another embodiment, R₃ is selected from D or (C₁-C₄)alkyl, optionally substituted with one to three R₁₈.

In another embodiment, two R₃ together when on adjacent carbons form a(C₃-C₈) cycloalkyl optionally substituted with one or more R₁₈. Inanother embodiment, two R₃ together when attached to the same carbonatom form a (C₃-C₈) spirocycloalkyl optionally substituted with one ormore R₁₈. In another embodiment, two R₃ together when attached to thesame carbon atom form a spiroheterocycloalkyl optionally substitutedwith one or more R₁₈. In another embodiment, two R₃ together when onadjacent carbons form an aryl ring optionally substituted with one ormore R₁₈. In another embodiment, two R₃ together when on adjacentcarbons form an heteroaryl ring optionally substituted with one or moreR₁₈.

In some embodiments of the Formulae above, R₄ is (C₁-C₆) alkyl, (C₆-C₁₄)aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein thealkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more R₁₂. In another embodiment, R₄ is (C₁-C₆)alkyl, (C₆-C₁₄) aryl, or heteroaryl wherein the alkyl, aryl, andheteroaryl are optionally substituted with one or more R₁₂. In anotherembodiment, R₄ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl andaryl are optionally substituted with one or more R₁₂.

In some embodiments of the Formulae above, R₅ is H, D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, halogen, or CN. In another embodiment, R₅ is H, D,(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, orhalogen. In yet another embodiment, R₅ is H, D, (C₁-C₃) alkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy, or halogen. In anotherembodiment, R₅ is H, D, (C₁-C₃) alkyl, or halogen. In yet anotherembodiment, R₅ is H, D, methyl, ethyl, propyl, iso-propyl, or halogen.

In some embodiments of the Formulae above, R_(5′) is H, D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, or CN. In another embodiment,R_(5′) is H, D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, or halogen. In yet another embodiment, R_(5′) is H,D, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy,or halogen. In another embodiment, R_(5′) is H, D, (C₁-C₃) alkyl, orhalogen. In yet another embodiment, R_(5′) is H, D, methyl, ethyl,propyl, iso-propyl, or halogen.

In some embodiments of the Formulae above, R₆ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆) haloalkyl. In anotherembodiment, R₆ is H, (C₁-C₃) alkyl, (C₂-C₃) alkenyl, (C₂-C₃) alkynyl, or(C₁-C₃) haloalkyl. In yet another embodiment, R₆ is H, (C₁-C₃) alkyl, or(C₁-C₃) haloalkyl. In another embodiment, R₆ is H or (C₁-C₃) alkyl. Inyet another embodiment, R₆ is H, methyl, ethyl, propyl, iso-propyl, orhalogen.

In some embodiments of the Formulae above, R₇ is H, D, (C₁-C₆) alkyl,halogen, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₄. Inanother embodiment, R₇ is H, D, (C₁-C₆) alkyl, halogen, (C₆-C₁₄) aryl,or heteroaryl, wherein the alkyl, aryl, and heteroaryl are optionallysubstituted with one or more R₁₄. In yet another embodiment, R₇ is H, D,(C₁-C₆) alkyl, (C₆-C₁₄) aryl, or heteroaryl, wherein the alkyl, aryl,and heteroaryl are optionally substituted with one or more R₁₄. Inanother embodiment, R₇ is H, D, (C₁-C₃) alkyl, (C₆-C₁₄) aryl, orheteroaryl, wherein the alkyl, aryl, and heteroaryl are optionallysubstituted with one or more R₁₄. In yet another embodiment, R₇ is H,(C₆-C₁₄) aryl, or heteroaryl, wherein the alkyl, aryl, and heteroarylare optionally substituted with one or more R₁₄.

In some embodiments of the Formulae above, R₈ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocycloalkyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, —C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀,—S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀, —NR₁₉S(O)_(q)R₂₀,—(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀, —NR₁₉C(O)C(O)R₂₀,—NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, or—OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₉. Inanother embodiment, R₈ is D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OR₁₉, CN, —C(O)R₁₉,—S(O)_(q)R₁₉, —(C₀-C₃)-alkylene-NR₁₉R₂₀, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉. In another embodiment, R₈ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OR₁₉,CN, —C(O)R₁₉, —S(O)_(q)R₁₉, —(C₀-C₃)-alkylene-NR₁₉R₂₀, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one to three R₉. In yet another embodiment, R₈ is D,(C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy,halogen, —OR₁₉, CN, —C(O)R₁₉, —S(O)_(q)R₁₉, —(C₀-C₃)-alkylene-NR₁₉R₂₀,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one to three R₉.

In another embodiment, two R₈ together when on adjacent atoms form a(C₃-C₈) cycloalkyl optionally substituted with one or more R₉. In yetanother embodiment, two R₈ together when on adjacent atoms form aheterocycloalkyl ring optionally substituted with one or more R₉. Inanother embodiment, two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉. In another embodiment,two R₈ together when on adjacent atoms form an heteroaryl ringoptionally substituted with one or more R₉.

In some embodiments of the Formulae above, R₉ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈)cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH,—C(O)R₂₁, —C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁,—S(O)_(q)NR₂₁R₂₂, —NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or —O-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₂₄. In another embodiment, R₉ is (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,—C(O)R₂₁, —S(O)_(q)R₂₁, —NR₂₁R₂₂, —OH, or CN. In yet another embodiment,R₉ is (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃)haloalkoxy, halogen, —C(O)R₂₁, —S(O)_(q)R₂₁, —NR₂₁R₂₂, —OH, or CN.

In some embodiments of the Formulae above, R₁₀ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one or more R₁₆. In another embodiment,R₁₀ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one to three R₁₆.In yet another embodiment, R₁₀ is H or (C₁-C₆) alkyl optionallysubstituted with one to three R₁₆.

In another embodiment, R₁₀ and R₁₁ together with the nitrogen to whichthey are attached form a heterocycloalkyl ring optionally substitutedwith one or more R₁₆.

In some embodiments of the Formulae above, R₁₁ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one or more R₁₆. In another embodiment,R₁₁ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one to three R₁₆.In yet another embodiment, R₁₁ is H or (C₁-C₆) alkyl optionallysubstituted with one to three R₁₆.

In some embodiments of the Formulae above, R₁₂ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₃. Inanother embodiment, R₁₂ is D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one to three R₁₃.

In another embodiment, two R₁₂ together when on adjacent atoms form a(C₃-C₈) cycloalkyl optionally substituted with one or more R₁₃. In yetanother embodiment, two R₁₂ together when on adjacent atoms form aheterocycloalkyl ring optionally substituted with one or more R₁₃. Inanother embodiment, two R₁₂ together when on adjacent atoms form an arylring optionally substituted with one or more R₁₃. In yet anotherembodiment, two R₁₂ together when on adjacent atoms form an heteroarylring optionally substituted with one or more R₁₃.

In some embodiments of the Formulae above, R₁₃ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂ (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₇. In another embodiment, R₁₃ is (C₁-C₃) alkyl,(C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy, halogen,—C(O)(C₁-C₃) alkyl, —S(O)_(q)(C₁-C₃) alkyl, (C₁-C₃) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one to three R₂₇.

In some embodiments of the Formulae above, R₁₄ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, —OH, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₅. Inanother embodiment, R₁₄ is (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, —OH, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one to three R₁₅.

In some embodiments of the Formulae above, R₁₅ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN. In another embodiment, R₁₅ is (C₁-C₃) alkyl, (C₁-C₃) alkoxy,(C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy, halogen, —C(O)(C₁-C₃) alkyl,—S(O)_(q)(C₁-C₃) alkyl, (C₁-C₃) alkylamino, di(C₁-C₃) alkylamino, —OH,or CN.

In some embodiments of the Formulae above, R₁₆ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆)hydroxyalkyl, —OH, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl,(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₁₇. In another embodiment, R₁₆ is (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆)hydroxyalkyl, —OH, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl,(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or three R₁₇. In yet another embodiment, R₁₆ is (C₁-C₃) alkyl,(C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy, halogen, (C₁-C₆)hydroxyalkyl, —OH, CN, —C(O)(C₁-C₃) alkyl, —S(O)_(q)(C₁-C₃) alkyl,(C₁-C₆) alkylamino, di(C₁-C₃) alkylamino, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or three R₁₇.

In some embodiments of the Formulae above, R₁₇ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN. In another embodiment, R₁₇ is (C₁-C₃) alkyl,(C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy, halogen,—C(O)(C₁-C₃) alkyl, —S(O)_(q)(C₁-C₃) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, —OH, or CN.

In some embodiments of the Formulae above, R₁₈ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN. In another embodiment, R₁₈ is (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkyl, (C₁-C₃) haloalkoxy, halogen, —OH, —NH₂, or CN.

In some embodiments of the Formulae above, R₁₉ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₃. In another embodiment, R₁₉ is H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₂₃.

In some embodiments of the Formulae above, R₂₀ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₃. In another embodiment, R₂₀ is H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R_(n).

In some embodiments of the Formulae above, R₂₁ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₃. In another embodiment, R₂₁ is H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R_(n).

In some embodiments of the Formulae above, R₂₂ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₃. In another embodiment, R₂₂ is H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₂₃.

In some embodiments of the Formulae above, R₂₃ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN. Inanother embodiment, R₂₃ is (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkyl, (C₁-C₃) haloalkoxy, halogen, —OH, or CN.

In some embodiments of the Formulae above, R₂₄ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆,—NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅,—S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN.

In some embodiments of the Formulae above, R₂₅ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl. In another embodiment, R₂₅ is H,(C₁-C₄) alkyl, (C₂-C₄) alkenyl, (C₂-C₄) alkynyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl.

In some embodiments of the Formulae above, R₂₆ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl. In another embodiment, R₂₆ is H,(C₁-C₄) alkyl, (C₂-C₄) alkenyl, (C₂-C₄) alkynyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl.

In some embodiments of the Formulate above, R₂₇ is (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, —OH, or CN. In another embodiment, R₂₇ is (C₁-C₄)alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen,—C(O)(C₁-C₄) alkyl, —S(O)_(q)(C₁-C₄) alkyl, —NH₂, (C₁-C₄) alkylamino,di(C₁-C₄) alkylamino, —OH, or CN.

In some embodiments of the Formulae above, m is 0, 1, 2, 3, or 4. Inanother embodiment, m is 0, 1, 2, or 3. In yet another embodiment, m is0, 1, or 2. In another embodiment, m is 0 or 1. In yet anotherembodiment, m is 0. In another embodiment, m is 1. In yet anotherembodiment, m is 2. In yet another embodiment, m is 3. In yet anotherembodiment, m is 4.

In some embodiments of the Formulae above, n is 0, 1, 2, or 3. Inanother embodiment, n is 0, 1, or 2. In yet another embodiment, n is 0or 1. In another embodiment, n is 0. In yet another embodiment, n is 1.In another embodiment, n is 2. In yet another embodiment, n is 3.

In some embodiments of the Formulae above, q is 0, 1, or 2. In anotherembodiment, q is 0. In yet another embodiment, q is 1. In anotherembodiment, q is 2.

In some embodiments of the formula above, X₁ is C.

In some embodiments of the formula above, X₂ is S and X₃ is N.

In some embodiments of the formula above, X₂ is NR₆ and X₃ is CR₇.

In some embodiments of the formula above, R₁ is OH.

In some embodiments of the formula above, R₄ is H(C₆-C₁₄) aryl, orheteroaryl.

In some embodiments of the formula above, R₅ is H.

In some embodiments of the formula above, R_(5′) is H.

In some embodiments of the formula above, R₆ is H.

In some embodiments of the formula above, R₇ is H.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and X₂ is C. In yet another embodiment, X₁ is C, X₂is C, and X₃ is N. In another embodiment, X₁ is C, X₂ is C, X₃ is N, andR₁ is OH. In yet another embodiment, X₁ is C, X₂ is C, X₃ is N, R₁ isOH, and R₂ is (C₁-C₄) alkyl, (C₆-C₁₄) aryl, or NR₁₀R₁₁, wherein thealkyl and aryl are optionally substituted with one or more R₈. Inanother embodiment, X₁ is C, X₂ is C, X₃ is N, R₁ is OH, R₂ is (C₁-C₄)alkyl, (C₆-C₁₄) aryl, or NR₁₀R₁₁, wherein the alkyl and aryl areoptionally substituted with one or more R₈, and R₄ is (C₁-C₆) alkyl or(C₆-C₁₄) aryl, wherein the alkyl and aryl are optionally substitutedwith one or more R₁₂. In yet another embodiment, X₁ is C, X₂ is C, X₃ isN, R₁ is OH, R₂ is (C₁-C₄) alkyl, (C₆-C₁₄) aryl, or NR₁₀R₁₁, wherein thealkyl and aryl are optionally substituted with one or more R₈, R₄ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₁₂, and R₅ is H. In anotherembodiment, X₁ is C, X₂ is C, X₃ is N, R₁ is OH, R₂ is (C₁-C₄) alkyl,(C₆-C₁₄) aryl, or NR₁₀R₁₁, wherein the alkyl and aryl are optionallysubstituted with one or more R₈, R₄ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl,wherein the alkyl and aryl are optionally substituted with one or moreR₁₂, R₅ is H, and R_(5′) is H.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and X₂ is N. In yet another embodiment, X₁ is C, X₂is N, and X₃ is CR₇. In another embodiment, X₁ is C, X₂ is N, X₃ is CR₇,and R₁ is OH. In yet another embodiment, X₁ is C, X₂ is N, X₃ is CR₇, R₁is OH and R₂ is (C₁-C₄) alkyl, (C₆-C₁₄) aryl, or NR₁₀R₁₁, wherein thealkyl and aryl are optionally substituted with one or more R₈. Inanother embodiment, X₁ is C, X₂ is N, X₃ is CR₇, R₁ is OH, R₂ is (C₁-C₄)alkyl, (C₆-C₁₄) aryl, or NR₁₀R₁₁, wherein the alkyl and aryl areoptionally substituted with one or more R₈, and R₄ is (C₁-C₆) alkyl or(C₆-C₁₄) aryl, wherein the alkyl and aryl are optionally substitutedwith one or more R₁₂. In another embodiment, X₁ is C, X₂ is N, X₃ isCR₇, R₁ is OH, R₂ is (C₁-C₄) alkyl, (C₆-C₁₄) aryl, or NR₁₀R₁₁, whereinthe alkyl and aryl are optionally substituted with one or more R₈, R₄ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₁₂, and R₅ is H. In anotherembodiment, X₁ is C, X₂ is N, X₃ is CR₇, R₁ is OH, R₂ is (C₁-C₄) alkyl,(C₆-C₁₄) aryl, or NR₁₀R₁₁, wherein the alkyl and aryl are optionallysubstituted with one or more R₈, R₄ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl,wherein the alkyl and aryl are optionally substituted with one or moreR₁₂, R₅ is H and R_(5.) is H. In yet another embodiment, X₁ is C, X₂ isN, X₃ is CR₇, R₁ is OH, R₂ is (C₁-C₄) alkyl, (C₆-C₁₄) aryl, or NR₁₀R₁₁,wherein the alkyl and aryl are optionally substituted with one or moreR₈, R₄ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₁₂, R₅ is H, R_(5.) is H, andR₇ is H.

Non-limiting illustrative compounds of the disclosure include:

-   6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-1);-   6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-methoxyphenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-2);-   3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-3);-   6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-[3-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-4);-   6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-fluorophenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one    (I-5);-   6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-methoxyphenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one    (I-6);-   6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-phenyl-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one    (I-7);-   6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-8);-   3-(4-fluoro-3-methoxyphenyl)-6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-9);-   3-(4-fluorophenyl)-6-({4-hydroxy-1-[5-(4-methylpiperazin-1-yl)pyridine-2-carbonyl]piperidin-4-yl}methyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-10);-   6-{[4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-11);-   6-({4-hydroxy-1-[(3S)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-12);-   6-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-13);-   6-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-14);-   6-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-15);-   6-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-16);-   6-{[1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-17);-   6-({1-[(3R)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-18);-   6-({1-[(3S)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-19);-   3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one    (I-20);-   6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-(4-methoxyphenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one    (I-21);-   4-({3-[4-fluoro-3-(piperazin-1-yl)phenyl]-7-oxo-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-6-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-22);-   6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-[4-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-23);-   6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-[4-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-24);-   3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-25);-   4-hydroxy-N,N-dimethyl-4-{[7-oxo-3-(4-{[2-(piperidin-1-yl)ethyl]amino}phenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]methyl}piperidine-1-carboxamide    (I-26);-   1-[2-(3-{6-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-7-oxo-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-3-yl}phenoxy)ethyl]imidazolidin-2-one    (I-27);-   3-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one    (I-28);-   6-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-3-phenyl-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one    (I-29);-   6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-fluorophenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-30); and-   6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-(4-methoxyphenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one    (I-31).

In another embodiment of the disclosure, the compounds of Formula (I)are enantiomers. In some embodiments the compounds are the(S)-enantiomer. In other embodiments the compounds are the(R)-enantiomer. In yet other embodiments, the compounds of Formula (I)may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent disclosure, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Compounds of the disclosure, and pharmaceutically acceptable salts,hydrates, solvates, stereoisomers and prodrugs thereof may exist intheir tautomeric form (for example, as an amide or imino ether). Allsuch tautomeric forms are contemplated herein as part of the presentdisclosure.

The compounds of the disclosure may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of thedisclosure as well as mixtures thereof, including racemic mixtures, formpart of the present disclosure. In addition, the present disclosureembraces all geometric and positional isomers. For example, if acompound of the disclosure incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the disclosure. Each compound herein disclosed includes allthe enantiomers that conform to the general structure of the compound.The compounds may be in a racemic or enantiomerically pure form, or anyother form in terms of stereochemistry. The assay results may reflectthe data collected for the racemic form, the enantiomerically pure form,or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the disclosure may be atropisomers (e.g.,substituted biaryls) and are considered as part of this disclosure.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the disclosure may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the disclosure. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the disclosure.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this disclosure, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the disclosure. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the disclosure.)Individual stereoisomers of the compounds of the disclosure may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present disclosure can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The compounds of Formula I may form salts which are also within thescope of this disclosure. Reference to a compound of the Formula hereinis understood to include reference to salts thereof, unless otherwiseindicated.

The present disclosure relates to compounds which are modulators ofUSP7. In one embodiment, the compounds of the present disclosure areinhibitors of USP7.

The disclosure is directed to compounds as described herein andpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, and pharmaceutical compositionscomprising one or more compounds as described herein, orpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

The compounds of the present disclosure may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds ofFormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present disclosure includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present disclosure can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present disclosure can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent disclosure can be synthesized by following the steps outlined inGeneral Schemes 1, 2, and 3 which comprise different sequences ofassembling intermediates Ia-Iw. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

wherein R₂-R₆, X₁, m, and n are defined as in Formula (I).

The general way of preparing compounds of Formula (I) by usingintermediates Ia, Ib, Ic, Id, Ie, If, and Ig is outlined in GeneralScheme 1. Reaction of Ia with piperidine and trimethoxyalkane, insolvent, e.g., dimethylformamide (DMF), at elevated temperaturesprovides intermediate Ib. Treatment of Ib with a strong acid, e.g.,hydrochloric acid in a solvent, e.g., water at elevated temperatureprovides intermediate Ic. Amination of Ic with an aminoacetate using anacid, e.g., para-toluenesulfonic acid, in a solvent, e.g., toluene, atelevated temperatures provides intermediate Id. Intermediate Ie can beobtained by treatment of Id with a base, e.g., sodium ethoxide, in asolvent, e.g., ethanol, at elevated temperatures. Hydrolysis of Ie witha base, e.g., lithium hydroxide, in a solvent, e.g., tetrahydrofuran andwater, provides carboxylic acid intermediate If. Coupling of acid If andamine Ih using a coupling reagent, e.g.,2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate Ig. Cyclization of Ig and trimethoxymethane optionally in asolvent at elevated temperature provides compounds of Formula (I).

wherein R₂-R₆, X₁, m, and n are defined as in Formula (I).

Alternatively, molecules of Formula I can be prepared usingintermediates Ii, Ij, Ik, IIa, IIb, Im, In, Io, and Iw as outlined inGeneral Scheme 2. Reduction of the nitro group in intermediate Ii withpalladium on carbon in solvent, e.g., methanol, under an atmosphere ofhydrogen gas provides intermediate Ij. Bromination of Ij usingN-bromosuccinamide in a solvent (e.g., tetrahydrofuran and/oracetonitrile) provides intermediate Ik. Coupling of Ik with anarylboronic acid or heteroarylboronic acid using a catalytic amount of apalladium catalyst, e.g., tetrakis[triphenylphosphine]palladium(0), anda base, e.g., tribasic potassium phosphate, in a solvent, e.g., dioxaneand/or water at elevated temperature provides a mixture of IIa and IIb.Intermediate Im is then prepared by cyclization of IIa and IIb andformamidine acetate salt in in a solvent, e.g., ethanol, at an elevatedtemperature. Alkylation of Im with Ivy using a base, e.g., cesiumcarbonate, in a solvent, e.g., dimethylformamide (DMF), yields In.Deprotection of intermediate In using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM)yields Io. Acylation of intermediate Io to produce a compound of Formula(I) where X₁ is C can be accomplished by coupling of an acid understandard coupling conditions using a coupling reagent, e.g.,2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compoundsof Formula (I). Alternatively, intermediate Io can be acylated with anacid chloride or carbamoyl chloride using a base, e.g., triethylamine orDIPEA, and in a solvent, e.g., dichloromethane, to produce a compound ofFormula (I) where X₁ is C. For synthesis of compounds of Formula (I)where X₁ is S or S(O), intermediate Io is treated with a sulfonylchloride or a sulfinic chloride and a base, e.g., triethylamine orN,N-diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane,DMF to provide the desired product of Formula (I).

wherein R₂-R₆, X₁, m, and n are defined as in Formula (I).

Molecules of Formula I can also be prepared using intermediates Ip, Iq,Ir, Is, It, Iu, Iv, and Ivy as outlined above in General Scheme 3.Reaction of Ip with a base, e.g., sodium ethoxide and isopentyl nitrite,in solvent provides intermediate Iq. Intermediate Ir is prepared byreacting Iq with 4-methylbenzenesulfonyl chloride and a base (e.g.,triethylamine) in a solvent (e.g., dichloromethane). Cyclization of Iswith ethyl 2-mercaptoacetate using a base, e.g., triethylamine, in asolvent, e.g., methanol provides intermediate Is. Intermediate It can beprepared by cyclizing Is and formamide optionally in solvent at elevatedtemperature. Alkylation of It with Iw using a base, e.g., cesiumcarbonate, in a solvent, e.g., dimethylformamide (DMF), yields Iu.Deprotection of intermediate Iu using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM)yields Iv. Acylation of intermediate Iv to produce a compound of Formula(I) where X₁ is C can be accomplished by coupling of an acid understandard coupling conditions using a coupling reagent, e.g.,2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compoundsof Formula (I). Alternatively, intermediate Iv, can be acylated with anacid chloride or carbamoyl chloride using a base, e.g., triethylamine orDIPEA, and in a solvent, e.g., dichloromethane, to produce a compound ofFormula (I) where X₁ is C. For synthesis of compounds of Formula (I)where X₁ is S or S(O), intermediate Iv is treated with a sulfonylchloride or a sulfinic chloride and a base, e.g., triethylamine orN,N-diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane,DMF to provide the desired product of Formula (I).

A mixture of enantiomers, diastereomers, cis/trans isomers resultingfrom the process described above can be separated into their singlecomponents by chiral salt technique, chromatography using normal phase,reverse phase or chiral column, depending on the nature of theseparation.

It should be understood that in the description and formula shown above,the various groups R₂-R₆, X₁, and other variables are as defined above,except where otherwise indicated. Furthermore, for synthetic purposes,the compounds of General Schemes 1, 2, and 3 are mere representativewith elected radicals to illustrate the general synthetic methodology ofthe compounds of Formula (I) as defined herein.

Methods of Using the Disclosed Compounds

Another aspect of the disclosure relates to a method of treating adisease or disorder associated with modulation of USP7. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of USP7 an effective amount thecompositions and compounds of Formula (I).

In another aspect, the present disclosure is directed to a method ofinhibiting USP7. The method involves administering to a patient in needthereof an effective amount of a compound of Formula (I).

Another aspect of the present disclosure relates to a method oftreating, preventing, inhibiting or eliminating a disease or disorder ina patient associated with the inhibition of USP7, the method comprisingadministering to a patient in need thereof an effective amount of acompound of Formula (I). In one embodiment, the disease or disorder isselected from the group consisting of cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present disclosure also relates to the use of an inhibitor of USP7for the preparation of a medicament used in the treatment, prevention,inhibition or elimination of a disease or condition mediated by USP7,wherein the medicament comprises a compound of Formula (I).

In another aspect, the present disclosure relates to a method for themanufacture of a medicament for treating, preventing, inhibiting, oreliminating a disease or condition mediated by USP7, wherein themedicament comprises a compound of Formula (I).

Another aspect of the present disclosure relates to a compound ofFormula (I) for use in the manufacture of a medicament for treating adisease associated with inhibiting USP7.

In another aspect, the present disclosure relates to the use of acompound of Formula (I) in the treatment of a disease associated withinhibiting USP7.

Another aspect of the disclosure relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I).

In another aspect, the present disclosure relates to a method oftreating a neurodegenerative disease. The method comprises administeringto a patient in need thereof an effective amount of a compound ofFormula (I).

Another aspect of the disclosure relates to a method of treating a viralinfection and disease. The method comprises administering to a patientin need thereof an effective amount of a compound of Formula (I).

In another aspect, the present disclosure relates to a method oftreating an inflammatory disease or condition. The method comprisesadministering to a patient in need thereof an effective amount of acompound of Formula (I).

Another aspect of the disclosure relates to a method of inducing cellcycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific Tcell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I).

In one embodiment, the present disclosure relates to the use of aninhibitor of USP7 for the preparation of a medicament used in treatment,prevention, inhibition or elimination of a disease or disorderassociated with associated with cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases.

In another embodiment, the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of cancers including, but not limited to, liposarcoma,neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer,multiple myeloma, colorectal cancer, non-small cell lung cancer, HumanPapilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroidor vaginal cancer or Epstein-Barr Virus-associated nasopharyngealcarcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkinlymphoma or diffuse large B-cell lymphoma.

In some embodiments, the patient is selected for treatment based on geneamplification and/or elevated tumor expression of USP7, MDM2 or MDM4relative to tissue-matched expression. In other embodiments, the patientis selected for the treatment based on tumor expression of wild typeTP53 or based on the tumor immune cell composition, specificallyelevated regulatory T lymphocytes, CD4+CD25+FoxP3+ T cells.

In some embodiments, administration of a compound of Formula (I) or apharmaceutical composition comprising a compound of the presentdisclosure and a pharmaceutically acceptable carrier induces a change inthe cell cycle or cell viability.

For example, the change in the cell cycle or cell viability may beindicated by decreased tumor levels of MDM2 protein and/or increasedlevels of TP53, CDKN1A (p21, Cip1), PUMA or BAX or by increasedexpression of one or more p53 target genes. In one embodiment, the p53target genes include, but are not limited to, CDKN1A (p21, Cip1), BBC3(PUMA), BAX or MDM2.

In another embodiment, the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of neurodegenerative diseases including, but not limitedto, Alzheimer's disease, multiple sclerosis, Huntington's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,amyotrophic lateral sclerosis, or encephalitis.

Another embodiment of the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of viral infections and diseases including but not limitedto, herpes simplex-1 or -2 viral infections, hepatitis A, hepatitis C,SARS coronavirus infection and disease, Epstein-Barr virus, rhinoviralinfections and diseases, adenoviral infections and diseases, orpoliomyelitis.

In another embodiment, the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of inflammatory diseases or conditions is associated withmetabolic disorders including, but not limited to, Type II diabetes,insulin resistance cardiovascular disease, arrhythmia, atherosclerosis,coronary artery disease, hypertriglyceridemia, dyslipidemia,retinopathy, nephropathy, neuropathy, or macular edema.

In another embodiment, the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of inflammatory diseases or conditions is associated withinflammatory bowel diseases including, but not limited to, ileitis,ulcerative colitis, Barrett's syndrome, or Crohn's disease

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of USP7 including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I).

One therapeutic use of the compounds or compositions of the presentdisclosure which inhibit USP7 is to provide treatment to patients orsubjects suffering from cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases.

The disclosed compounds of the disclosure can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Disclosure and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564 which ishereby incorporated by reference in its entirety.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker or Varian spectrometers at 300 or 400MHz. Spectra are given in ppm (δ) and coupling constants, J, arereported in Hertz. Tetramethylsilane (TMS) was used as an internalstandard. Mass spectra were collected using a Waters ZQ Single Quad MassSpectrometer (ion trap electrospray ionization (ESI)). Purity and lowresolution mass spectral data were measured using Waters Acquity i-classultra-performance liquid chromatography (UPLC) system with Acquity PhotoDiode Array Detector, Acquity Evaporative Light Scattering Detector(ELSD) and Waters ZQ Mass Spectrometer. Data was acquired using WatersMassLynx 4.1 software and purity characterized by UV wavelength 220 nm,evaporative light scattering detection (ELSD) and electrospray positiveion (ESI). (Column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow rate 0.6mL/min; Solvent A (95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/FormicAcid), Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); gradient:5-100% B from 0 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21mins. Preparatory HPLC purifications were conducted on a Waters SunFireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm, Waters)(Bridge BEH C18OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm with UV detection (Waters 2489UV/998 PDA), Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×150mm, Waters)(Bridge BEH Shield RP18 OBD Prep Column, 130 Å, 5 μm, 19mm×150 mm, or Waters XSelect CSH C18 OBD Prep Column, 130 Å, 5 μm, 19mm×150 mm at 254 nm or 220 nm using a standard solvent gradient program(or as designated below).

Abbreviations used in the following examples and elsewhere herein are:

-   -   atm atmosphere    -   br broad    -   DEAD diisopropyl azodicarboxylate    -   DIPEA N,N-diisopropylethylamine    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   EI electron ionization    -   ESI electrospray ionization    -   Et ethyl    -   h hour(s)    -   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HPLC high-performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   m multiplet    -   Me methyl    -   MHz megahertz    -   min minutes    -   MW microwave    -   NMR nuclear magnetic resonance    -   ppm parts per million    -   s singlet    -   Sphos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl    -   TFA trifluoroacetic acid    -   TLC thin layer chromatography    -   v volume    -   wt weight

Example 1 Intermediate 2-1.(4-Methoxyphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl) methanone

Trimethylsulfoxonium iodide (3.17 g, 14.4 mmol), sodium hydride (60% inmineral oil, 576 mg, 14.4 mmol), and dimethyl sulfoxide (15 mL) wereadded to a 100-mL round-bottom flask fitted with a nitrogen inlet andmagnetic stir bar. The resulting mixture was stirred for 30 min at 0° C.1-(4-Methoxybenzoyl)piperidin-4-one (1.12 g, 4.81 mmol) was added andstirring was continued for an additional 2 h at room temperature. Thereaction was quenched by the addition of water (100 mL) and extractedwith dichloromethane (3×100 mL). The organic layers were combined, driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:1 v/v) to afford(4-methoxyphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone(Intermediate 2-1, 0.84 g, 71%). LCMS: (ESI) m/z 248 [M+H].

TABLE 1 The Intermediates in Table 1 were synthesized according to theprocedure described in Example 1 above. LCMS: (ESI) m/z IntermediateNo.: Precursor used [M + H] Intermediate 2-2. (4-Fluoro- 1-(4-Fluoro-236 phenyl)(1-oxa-6-azaspiro[2.5]octan- benzoyl)piperidin-6-yl)methanone 4-one Intermediate 2-3. Phenyl(1-oxa-6-1-benzoylpiperidin- 218 azaspiro[2.5]octan-6-yl)methanone 4-one

Example 2 Intermediate 2-4.3-(4-Fluorophenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

Step 1. 4-Fluoro-N-hydroxybenzimidoyl cyanide (Mixture of Syn and AntiIsomers)

2-(4-Fluorophenyl)acetonitrile (2.00 g, 14.8 mmol), ethanol (30 mL),sodium ethoxide (21 wt % in ethanol, 15 mL, 40.2 mmol) and isopentylnitrite (5.20 g, 44.4 mmol) were added to a 100-mL round-bottom flaskfitted with magnetic stir bar. The resulting solution was stirred for 16h at room temperature. The resulting mixture was concentrated underreduced pressure and the residue was partitioned between ethyl acetate(100 mL) and water (100 mL). The layers were separated and the aqueousphase was further extracted with ethyl acetate (2×100 mL). The organiclayers were combined, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to afford4-fluoro-N-hydroxybenzimidoyl cyanide (mixture of syn and anti isomers)which was used in the next step without further purification orcharacterization. ¹H NMR (300 MHz, DMSO-d₆) δ 7.74-7.67 (m, 2H),7.36-7.25 (m, 2H) ppm.

Step 2. 4-Fluoro-N-(tosyloxy)benzimidoyl cyanide (Mixture of Syn andAnti Isomers)

4-Fluoro-N-hydroxybenzimidoyl cyanide (mixture of syn and anti isomers,Step 1), triethylamine (3.30 g, 32.6 mmol), dichloromethane (20 mL), and4-methylbenzenesulfonyl chloride (3.10 g, 16.3 mmol) were added to a100-mL round-bottom flask fitted with a magnetic stir bar. The resultingsolution was stirred for 3 h at room temperature, then diluted withwater (50 mL), and extracted with dichloromethane (3×50 mL). The organiclayers were combined, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:5 v/v) toafford 4-fluoro-N-(tosyloxy)benzimidoyl cyanide (mixture of syn and antiisomers, 900 mg, 26% over two steps). LCMS: (ESI) m/z 319 [M+H].

Step 3. Ethyl 4-amino-3-(4-fluorophenyl)isothiazole-5-carboxylate

4-Fluoro-N-(tosyloxy)benzimidoyl cyanide (mixture of syn and antiisomers, Step 2, 500 mg, 1.57 mmol), triethylamine (476 mg, 4.70 mmol),methanol (20 mL), and ethyl 2-mercaptoacetate (283 mg, 2.35 mmol) wereadded to a 100-mL round-bottom flask fitted with a magnetic stir bar.The resulting solution was stirred for 2 h at room temperature and thenconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:3 v/v) toafford ethyl 4-amino-3-(4-fluorophenyl)isothiazole-5-carboxylate (300mg, 72%). LCMS: (ESI) m/z 267 [M+H].

Step 4. 3-(4-Fluorophenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

Ethyl 4-amino-3-(4-fluorophenyl)isothiazole-5-carboxylate (Step 3, 300mg, 1.13 mmol) and formamide (15 mL) were added to a 100-mL round-bottomflask fitted with magnetic stir bar, condenser and thermometer. Theresulting solution was stirred for 16 h at 140° C., quenched by theaddition of water (50 mL), and then extracted with ethyl acetate (5×50mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography eluting with ethylacetate/petroleum ether (1:1 v/v) to afford3-(4-fluorophenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate2-4, 260 mg, 93%). LCMS: (ESI) m/z 248 [M+H].

TABLE 2 The Intermediates in Table 2 were synthesized according to theprocedure described in Example 2 above. LCMS: (ESI) m/z IntermediateNo.: Precursor used [M + H] Intermediate 2-5. 3-(4- 2-(4-Methoxy- 260Methoxyphenyl)isothiazolo[4,5- phenyl)acetonitrile d]pyrimidin-7(6H)-oneIntermediate 2-6. 3-(4-fluoro-3- 2-(4-fluoro-3-methoxy- 278methoxyphenyl)isothiazolo[4,5- phenyl)acetonitrile d]pyrimidin-7(6H)-oneIntermediate 2-7. 3- 2-phenylacetonitrile 230Phenylisothiazolo[4,5-d]pyrimidin- 7(6H)-one Intermediate 2-8.3-(3-bromo-4- 2-(3-bromo-4-fluoro- 326 fluorophenyl)isothiazolo[4,5-phenyl)acetonitrile d]pyrimidin-7(6H)-one Intermediate 2-9. 3-(4-2-(4-bromo- 308, 310 bromophenyl)isothiazolo[4,5- phenyl)acetonitriled]pyrimidin-7(6H)-one Intermediate 2-10. 3-(3- 2-(3-methoxy- 260methoxyphenyl)isothiazolo[4,5- phenyl)acetonitrile d]pyrimidin-7(6H)-one

Example 3 Intermediate 2-11.3-(3-(Hydroxymethyl)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

Step 1. N-Hydroxy-3-methylbenzimidoyl cyanide (Mixture of Syn and AntiIsomers)

2-(m-Tolyl)acetonitrile (2.00 g, 15.3 mmol), ethanol (15 mL), isopentylnitrite (5 mL), and sodium ethoxide (21 wt % in ethanol, 20 mL, 53.6mmol) were added to a 100-mL round-bottom flask with a magnetic stirbar. The resulting mixture was stirred for 16 h at room temperature. Theresulting solution was then diluted with water (100 mL) and extractedwith ethyl acetate (3×50 mL). The organic layers were combined, driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford N-hydroxy-3-methylbenzimidoyl cyanide (mixture of synand anti isomers) which was used in next step without furtherpurification. GCMS: (EI) m/z 160 [M].

Step 2. 3-Methyl-N-(tosyloxy)benzimidoyl cyanide (Mixture of Syn andAnti Isomers)

N-Hydroxy-3-methylbenzimidoyl cyanide (mixture of syn and anti isomers,Step 1), dichloromethane (60 mL), 4-methylbenzene-1-sulfonyl chloride(5.00 g, 26.2 mmol), and triethylamine (15 mL) were added to a 250-mLround-bottom flask fitted with a magnetic stir bar. The resultingsolution was stirred for 3 h at room temperature and then concentratedunder reduced pressure. The residue was partitioned betweendichloromethane (50 mL) and water (100 mL). The layers were separatedand the aqueous phase was further extracted with dichloromethane (2×50mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to afford3-methyl-N-(tosyloxy)benzimidoyl cyanide (mixture of syn and antiisomers) which was used without further purification. LCMS: (ESI) m/z315 [M+H].

Step 3. Ethyl 4-amino-3-(m-tolyl)isothiazole-5-carboxylate

3-Methyl-N-(tosyloxy)benzimidoyl cyanide (mixture of syn and antiisomers, Step 2), methanol (60 mL), ethyl 2-mercaptoacetate (3.50 g,29.1 mmol), and triethylamine (10 mL) were added to a 250-mLround-bottom flask with a magnetic stir bar. The resulting solution wasstirred for 2 h at room temperature and then concentrated under reducedpressure. The residue was purified by column chromatography eluting withethyl acetate/petroleum (1:1 v/v) to afford ethyl4-amino-3-(m-tolyl)isothiazole-5-carboxylate (4.00 g, 100% over 3steps). LCMS: (ESI) m/z 263 [M+H].

Step 4. 3-(m-Tolyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

Ethyl 4-amino-3-(m-tolyl)isothiazole-5-carboxylate (Step 3, 2.00 g, 7.62mmol) and formamide (20 mL) were added to a 100-mL round-bottom flaskfitted with a magnetic stir bar and condenser. The resulting solutionwas stirred for 16 h at 140° C. The mixture was then cooled to roomtemperature, diluted with water (60 mL) and extracted with ethyl acetate(3×50 mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with ethylacetate/petroleum (1:1 v/v) to afford3-(m-tolyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (400 mg, 22%). LCMS:(ESI) m/z 244 [M+H].

Step 5. 3-(3-(Bromomethyl)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

3-(m-Tolyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (Step 4, 400 mg, 1.64mmol) carbon tetrachloride (20 mL), N-bromosuccinimide (540 mg, 3.03mmol), and benzoyl peroxide (450 mg, 1.76 mmol) were added to a 100-mLround-bottom flask fitted with a magnetic stir bar and condenser. Theresulting solution was purged and maintained under an atmosphere ofnitrogen and then stirred for 16 h at 80° C. The mixture wasconcentrated under reduced pressure. The resulting residue was dilutedwith water (100 mL) and extracted with dichloromethane (3×50 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified via silica gel column chromatography eluting with ethylacetate/petroleum ether (1:1 v/v) to afford3-(3-(bromomethyl)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (275 mg,52%). LCMS: (ESI) m/z 322 [M+H].

Step 6. 3-(3-(Hydroxymethyl)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

3-(3-(Bromomethyl)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (200 mg,0.62 mmol), water (8 mL), 1,4-dioxane (8 mL), and calcium carbonate (600mg, 5.99 mmol) were added to a 100-mL round-bottom flask fitted with amagnetic stir bar and condenser. The resulting solution was stirred for2 h at 100° C. and then concentrated under reduced pressure. The residuewas diluted with water (100 mL) and extracted with ethyl acetate (3×20mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified via silica gel column chromatography eluting with ethylacetate/petroleum ether (1:1 v/v) to afford 3-(3-(hydroxymethyl)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate 2-11, 100 mg,62%). LCMS: (ESI) m/z 260 [M+H].

TABLE 3 The Intermediates in Table 3 were synthesized according to theprocedure described in Example 3 above. LCMS: (ESI) m/z IntermediateNo.: Precursor used [M + H] Intermediate 2-12. 3-(4- — 260(hydroxymethyl)phenyl)isothia- zolo[4,5-d]pyrimidin-7(6H)-one

Example 4 Intermediate 2-13.(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl) methanone

(4-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone, 500 mg, 2.13mmol), methanol (20 mL), and ammonia (7.0 M solution in methanol, 5 mL)were added to a 100-mL sealed tube fitted with a magnetic stir bar. Theresulting solution was stirred for 3 h at room temperature and thenconcentrated under reduced pressure to afford(4-(aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl)methanone(Intermediate 2-13) which was used without any purification. LCMS: (ESI)m/z 253 [M+H].

TABLE 4 The Intermediate in Table 4 was synthesized according to theprocedure described in Example 4 above. LCMS: (ESI) m/z IntermediateNo.: Precursor used [M + H] Intermediate 2-14. (4-(amino-(4-methoxyphenyl)(1-oxa- 265 methyl)-4-hydroxypiperidin-1-6-azaspiro[2.5]octan-6- yl)(4-methoxyphenyl)methanone yl)methanone, 2-2

Example 5 Intermediate 2-15.(R)-5-allyl-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

Step 1. 5-Allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (1.20 g, 7.81 mmol),3-bromoprop-1-ene (1.86 g, 15.4 mmol), and DMF (40 mL) were added to a100-mL round-bottom flask fitted with a nitrogen inlet and magnetic stirbar. Sodium hydride (625 mg, 26.0 mmol) was added in portions and theresulting solution was stirred for 20 min at room temperature. Thereaction was then quenched by the addition of water (40 mL) andextracted with ethyl acetate (3×50 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified via silicagel column chromatography eluting with ethyl acetate/petroleum ether(3:10, v/v) to afford 5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.30g, 86%). LCMS: (ESI) m/z 194 [M+H].

Step 2. 5-Allyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

5-Allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (Step 1, 650 mg, 3.36mmol), 1,4-dioxane (20 mL), and a solution of sodium hydroxide (1.80 g,45.0 mmol) in water (20 mL) were added to a 100-mL 3-necked round-bottomflask fitted with a magnetic stir bar, condenser, and thermometer. Theresulting solution was stirred for 2 h at 100° C. and then cooled toroom temperature and extracted with ethyl acetate (3×50 mL). The organiclayers were combined, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedvia silica gel column chromatography eluting with ethylacetate/petroleum ether (1:5, v/v) to afford5-allyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (0.48 g, 82%).LCMS: (ESI) m/z 176 [M+H].

Step 3. tert-Butyl4-((5-allyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate

5-Allyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (Step 2, 600 mg,3.42 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (873mg, 4.09 mmol), cesium carbonate (3.36 g, 10.3 mmol), and DMF (30 mL)were added to a 100-mL 3-necked round-bottom flask fitted with amagnetic stir bar, condenser, and thermometer. The resulting mixture wasstirred for 2 h at 80° C. Water (100 mL) was then added at roomtemperature and the resulting solution was extracted with methyltert-butyl ether (4×100 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford tert-butyl4-((5-allyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylatewhich was used in the next step without further purification. LCMS:(ESI) m/z 389 [M+H].

Step 4.5-Allyl-3-((4-hydroxypiperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-onetrifluoroacetic acid

tert-Butyl4-((5-allyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate(Step 3), TFA (5 mL), and dichloromethane (5 mL) were added to a 100-mLround-bottom flask fitted with a magnetic stir bar. The resultingsolution was stirred for 2 h at room temperature then concentrated underreduced pressure to afford5-allyl-3-((4-hydroxypiperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-onetrifluoroacetic acid (600 mg) which was used without furtherpurification. LCMS: (ESI) m/z 289 [M+H].

Step 5.(R)-5-Allyl-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

5-Allyl-3-((4-hydroxypiperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-onetrifluoroacetic acid (Step 4, 225 mg), (R)-3-phenylbutanoic acid (148mg, 0.90 mmol), HATU (205 mg, 0.54 mmol), DIPEA (232 mg, 1.80 mmol), anddichloromethane (20 mL) were added to a 50 mL round-bottom flask fittedwith a magnetic stir bar. The resulting solution was stirred for 2 h at50° C. Water (20 mL) was added at room temperature and the resultingsolution was extracted with ethyl acetate (3×30 mL). The organic layerswere combined, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography eluting with ethyl acetate to afford(R)-5-allyl-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one(Intermediate 2-15, 160 mg, 29% over three steps). LCMS: (ESI) m/z 435[M+H].

Example 6 Intermediate 2-16. 3-(difluoromethoxy)cyclobutanecarboxylicacid

Step 1. Methyl 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate

A 50-mL round-bottom flask fitted with a nitrogen inlet, a magnetic stirbar, a thermometer, and a condenser was charged with methyl5-bromopyridine-2-carboxylate (300 mg, 1.39 mmol), 1-methylpiperazine(167 mg, 1.67 mmol), potassium phosphate (416 mg, 1.96 mmol), toluene(10 mL), Sphos (11.5 mg, 0.03 mmol), and Pd₂(dba)₃ (7.2 mg, 0.01 mmol).The resulting solution was stirred for 16 h at 110° C. in an oil bathand then cooled to 23° C. The resulting mixture was diluted with water(30 mL) and the product was extracted with ethyl acetate (6×30 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography eluting with ethylacetate/petroleum ether (3:7 v/v) to afford methyl5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate (130 mg, 33%). LCMS:(ESI) m/z 236 [M+H].

Step 2. 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylic acid

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwith methyl 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate (Step 1,130 mg, 0.55 mmol), methanol (10 mL), lithium hydroxide (40 mg, 1.67mmol), and water (2 mL). The solution was stirred for 16 h at 23° C. andconcentrated under reduced pressure. The residue was diluted with water(10 mL) and the pH was adjusted to 6 with hydrochloric acid (3N). Thesolids were collected by filtration and dried in an oven to afford5-(4-methylpiperazin-1-yl)pyridine-2-carboxylic acid (Intermediate 2-16,90 mg, 74%). LCMS (ESI) m/z 222 [M+H].

Example 7 Intermediate 2-17. 4,4-difluoro-3-phenylbutanoic acid

Step 1. (E)-Methyl 4,4-difluoro-3-phenylbut-2-enoate

A 100-mL 3-necked round-bottom flask fitted with a nitrogen inlet, amagnetic stir bar, a thermometer, and a condenser was charged with2,2-difluoro-1-phenylethan-1-one (300 mg, 1.92 mmol), methyl2-(triphenyl-5-phosphanylidene)acetate (963.5 mg, 2.88 mmol), andtoluene (30 mL). The resulting solution was stirred overnight at 110° C.in an oil bath and then cooled to 23° C. The reaction mixture wasconcentrated under reduced pressure and dissolved in water (50 mL). Theproduct was extracted with ethyl acetate (3×40 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtrated, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:2 v/v) toafford (E)-methyl 4,4-difluoro-3-phenylbut-2-enoate (400 mg, 98%) as acolorless oil. LCMS: (ESI) m/z 213 [M+H].

Step 2. Methyl 4,4-difluoro-3-phenylbutanoate

A 100-mL round-bottom flask fitted with a hydrogen balloon and magneticstir bar was charged with (E)-methyl 4,4-difluoro-3-phenylbut-2-enoate(Step 1, 400 mg, 1.89 mmol, 1.00 equiv), palladium on carbon (10% wt, 50mg), and methanol (20 mL). The resulting mixture was stirred overnightat room temperature. The reaction solution was then filtered and thefiltrate was concentrated under reduced pressure to provide methyl4,4-difluoro-3-phenylbutanoate which was used in next step withoutfurther purification. GCMS (m/z): 214

Step 3. 4,4-Difluoro-3-phenylbutanoic acid

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwith methyl 4,4-difluoro-3-phenylbutanoate (Step 2, 330 mg, 1.54 mmol),lithium hydroxide (50 mg, 2.09 mmol), and methanol (30 mL). Theresulting mixture was stirred for 16 h at 23° C. The reaction was thenconcentrated under reduced pressure and diluted with water (10 mL). ThepH was adjusted to 2 with hydrochloric acid (6N) and the solids werecollected by filtration to provide 4,4-difluoro-3-phenylbutanoic acid(Intermediate 2-17, 280 mg, 91%). LCMS: (ESI) m/z 201 [M+H].

Example 8 Intermediate 2-18.3-Phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

Step 1. Ethyl 4-amino-1H-pyrazole-5-carboxylate

Ethyl 4-nitro-1H-pyrazole-5-carboxylate (1.00 g, 5.40 mmol), palladiumon carbon (10% wt, 300 mg), and methanol (30 mL) were added to a 100-mLround-bottom flask fitted with a magnetic stir bar. The mixture waspurged with hydrogen and then stirred for 4 h at room temperature. Thereaction mixture was then filtered and concentrated under reducedpressure to afford ethyl 4-amino-1H-pyrazole-5-carboxylate (900 mg)which was used without further purification. LCMS: (ESI) m/z 156 [M+H].

Step 2. Ethyl 4-amino-1H-pyrazole-5-carboxylate

A solution of N-bromosuccinimide (630 mg, 3.54 mmol) in tetrahydrofuran(15 mL) was added dropwise to a solution of ethyl4-amino-1H-pyrazole-5-carboxylate (Step 1, 500 mg, 3.22 mmol) inacetonitrile (50 mL) at 0° C. The resulting solution was stirred for 2 hat 0° C. and then concentrated under reduced pressure. The residue waspurified by preparative TLC eluting with methanol/dichloromethane (1:20v/v) to afford ethyl 4-amino-1H-pyrazole-5-carboxylate (450 mg, 60%).LCMS: (ESI) m/z 234, 236 [M+H].

Step 3. Ethyl 4-amino-3-phenyl-1H-pyrazole-5-carboxylate and4-amino-3-phenyl-1H-pyrazole-5-carboxylic acid

4-Amino-1H-pyrazole-5-carboxylate (350 mg, 1.50 mmol), phenylboronicacid (219 mg, 1.80 mmol), tetrakis[triphenylphosphine]palladium(0) (173mg, 0.15 mmol), tribasic potassium phosphate (951 mg, 4.48 mmol),1,4-dioxane (50 mL), and water (10 mL) were added to a 100 mLround-bottom flask fitted with a nitrogen inlet, magnetic stir bar andcondenser. The reaction was stirred overnight at 100° C. and thenconcentrated under reduced pressure. The residue was purified bypreparative TLC eluting with methanol/dichloromethane (1:20 v/v) toafford ethyl 4-amino-3-phenyl-1H-pyrazole-5-carboxylate (150 mg,impurities present). LCMS: (ESI) m/z 232 [M+H] and4-amino-3-phenyl-1H-pyrazole-5-carboxylic acid (200 mg, impuritiespresent). LCMS: (ESI) m/z 204 [M+H].

Step 4. 3-Phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

Ethyl 4-amino-3-phenyl-1H-pyrazole-5-carboxylate (Step 3, 150 mg) and4-amino-3-phenyl-1H-pyrazole-5-carboxylic acid (Step 3, 200 mg),formamidine acetate salt (768 mg, 7.38 mmol), and ethanol (30 mL) wereadded to a 100-mL round-bottom flask fitted with a nitrogen inlet,magnetic stir bar and condenser. The resulting solution was heated atreflux overnight and then concentrated under reduced pressure. Theresidue was purified by column chromatography eluting withdichloromethane/methanol (10:1 v/v) to afford3-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Intermediate2-18, 250 mg, 79% over two steps). LCMS: (ESI) m/z 213 [M+H].

TABLE 5 The Intermediates in Table 5 were synthesized according to theprocedure described in Example 8 above. LCMS: (ESI) m/z IntermediateNo.: Precursor used [M + H] Intermediate 2-19. 3-(4-fluoro- — 231phenyl)-1H-pyrazolo[4,3-d]pyrimidin- 7 (6H)-one Intermediate 2-20.3-(4-methoxy- — 243 phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

Example 9 Intermediate 2-21.6-((4-Hydroxypiperidin-4-yl)methyl)-3-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-onetrifluoroacetic acid salt

Step 1. tert-Butyl4-hydroxy-4-((7-oxo-3-phenyl-1,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)methyl)piperidine-1-carboxylate

3-Phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (200 mg, 0.94mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (300 mg,1.41 mmol), cesium carbonate (924 mg, 2.84 mmol), and DMF (50 mL) wereadded to a 100-mL round-bottom flask fitted with a nitrogen inlet,magnetic stir bar and condenser. The reaction mixture was stirred for 5h at 80° C. and then quenched by the addition of water (50 mL). Theresulting solution was extracted with ethyl acetate (4×50 mL). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by preparative TLC eluting withdichloromethane/methanol (20:1 v/v) to afford tert-butyl4-hydroxy-4-((7-oxo-3-phenyl-1,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)methyl) piperidine-1-carboxylate (60 mg, 15%).LCMS: (ESI) m/z 426 [M+H].

Step 2.6-((4-Hydroxypiperidin-4-yl)methyl)-3-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-onetrifluoroacetic acid salt

tert-Butyl 4-hydroxy-4-((7-oxo-3-phenyl-1,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)methyl)piperidine-1-carboxylate(Step 1, 60 mg, 0.14 mmol), TFA (2 mL), and dichloromethane (30 mL) wereadded to a 100-mL round-bottom flask fitted with a nitrogen inlet andmagnetic stir bar. The resulting solution was stirred for 1 h at roomtemperature and then concentrated under reduced pressure to afford6-((4-hydroxypiperidin-4-yl)methyl)-3-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-onetrifluoroacetic acid salt (Intermediate 2-21, 80 mg, >95%) which wasused without further purification. LCMS: (ESI) m/z 326 [M+H].

Example 10 Intermediate 2-22. ethyl4-(ethoxymethyleneamino)-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate

Step 1. ethyl 4-amino-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate

A 3-necked 100-mL round-bottom flask fitted a nitrogen inlet, magneticstir bar, thermometer and condenser was charged with ethyl4-amino-3-bromo-1H-pyrazole-5-carboxylate (600 mg, 2.56 mmol),4-methoxyphenylboronic acid (586 mg, 3.86 mmol), Pd(PPh₃)₄ (296 mg, 0.26mmol), K₃PO₄ (1630 mg, 7.68 mmol), dioxane (50 mL), and water (5 mL).The resulting solution was stirred overnight at 100° C. in an oil bathand then allowed to cool to 23° C. The reaction was then quenched withwater (20 mL) and the product was extracted with ethyl acetate (5×30mL). The organic layers were combined and washed with brine (50 mL),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by preparatory TLC elutingwith ethyl acetate/petroleum ether (2:1 v/v) to afford ethyl4-amino-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate (350 mg, 52%).LCMS (ESI) m/z 262 [M+H].

Step 2. ethyl4-(ethoxymethyleneamino)-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate

A 100-mL 3-necked round-bottom flask fitted a nitrogen inlet, magneticstir bar, thermometer and condenser was charged with ethyl4-amino-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate (Step 1, 100 mg,0.38 mmol), TsOH (5 mg, 0.03 mmol), and (C₂H₅O)₃CH (20 mL). The solutionwas stirred for 2 h at 90° C. in an oil bath and cooled to 23° C. Thereaction was quenched with water (20 mL) and the product was extractedwith ethyl acetate (5×30 mL). The combined organic layers were thenwashed with brine (30 mL). The organic phase was dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresulting mixture was concentrated under reduced pressure to give ethyl4-(ethoxymethyleneamino)-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate(Intermediate 2-22, 120 mg, 99%) used without further purification. LCMS(ESI) m/z 318 [M+H].

TABLE 6 The Intermediate in Table 6 was synthesized according to theprocedure described in Example 10 above. LCMS: (ESI) m/z IntermediateNo.: Precursor used [M + H] Intermediate 2-23. ethyl (E)-4- ethyl4-amino-3- 288 ((ethoxymethylene)amino)-3- bromo-1H-pyrazole-phenyl-1H-pyrazole-5-carboxylate 5-carboxylate

Methods for the Synthesis of Compounds of Formula (I) Method A Example116-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-phenylisothiazolo[4,5-d]pyrimidin-7(6H)-one(I-1)

Step 1. tert-Butyl4-hydroxy-4-((7-oxo-3-phenylisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxylate

3-Phenylisothiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate 2-7, 100 mg,0.44 mmol), cesium carbonate (213 mg, 0.65 mmol), DMF (10 mL), andtert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (140 mg, 0.65 mmol)were added to a 100-mL round-bottom flask fitted with magnetic stir bar,condenser and thermometer. The resulting mixture was stirred for 3 h at80° C. The reaction was quenched by the addition of water (20 mL) andextracted with dichloromethane (3×20 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:1 v/v) toafford tert-butyl4-hydroxy-4-((7-oxo-3-phenylisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxylate(110 mg, 57%). LCMS: (ESI) m/z 443 [M+H].

Step 2.6-((4-Hydroxypiperidin-4-yl)methyl)-3-phenylisothiazolo[4,5-d]pyrimidin-7(6H)-onetrifluoroacetic acid salt

tert-Butyl4-hydroxy-4-((7-oxo-3-phenylisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxylate (Step 1, 110 mg, 0.25 mmol), TFA (1 mL),and dichloromethane (15 mL) were added to a 100-mL round-bottom flaskfitted with magnetic stir bar. The resulting solution was stirred for 2h at room temperature and then concentrated under reduced pressure toafford6-((4-hydroxypiperidin-4-yl)methyl)-3-phenylisothiazolo[4,5-d]pyrimidin-7(6H)-onetrifluoroacetic acid salt which was used without further purification.LCMS: (ESI) m/z 343 [M+H].

Step 3.6-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-phenylisothiazolo[4,5-d]pyrimidin-7(6H)-one

6-((4-Hydroxypiperidin-4-yl)methyl)-3-phenylisothiazolo[4,5-d]pyrimidin-7(6H)-onetrifluoroacetic acid salt (Step 2), HATU (156 mg, 0.41 mmol), DIPEA (106mg), dichloromethane (10 mL), and 4-fluorobenzoic acid (57 mg, 0.41mmol) were added to a 100-mL round-bottom flask fitted with magneticstir bar. The resulting solution was stirred for 2 h at roomtemperature, diluted with water (30 mL), and then extracted with ethylacetate (3×30 mL). The combined organic phases were dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by preparative HPLC to afford6-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-phenylisothiazolo[4,5-d]pyrimidin-7(6H)-one(I-1). LCMS: (ESI) m/z 465.19 [M+H]. ¹H NMR (400 MHz, dmso-d₆) δ8.47-8.42 (m, 3H), 7.60-7.54 (m, 3H), 7.49-7.47 (m, 2H), 7.29-7.25 (m,2H), 5.07 (s, 1H), 4.28-4.13 (m, 3H), 3.45-3.06 (m, 3H), 1.75-1.31 (m,4H) ppm. HPLC Column: Waters XBridge BEH Shield RP18 OBD Prep Column,130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 0.05% aqueous ammoniumbicarbonate/Mobile phase B: acetonitrile. Gradient: 3.5% B to 8.2% Bover 8 min.

Method B Example 126-((4-Hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl)methyl)-3-phenylisothiazolo[4,5-d]pyrimidin-7(6H)-one(I-8)

3-Phenylisothiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate 2-7, 50 mg,0.22 mmol), cesium carbonate (215 mg, 0.66 mmol), DMF (10 mL), and(4-methoxyphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone(Intermediate 2-1, 65 mg, 0.26 mmol) were added to a 100-mL round-bottomflask fitted with magnetic stir bar, condenser, and thermometer. Theresulting mixture was stirred for 2.5 h at 80° C. The reaction wasquenched by the addition of water (20 mL) and extracted with ethylacetate (4×20 mL). The organic layers were combined, dried with sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by preparative HPLC to afford6-((4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl)methyl)-3-phenylisothiazolo[4,5-d]pyrimidin-7(6H)-one(I-2). LCMS: (ESI) m/z 477.27 [M+H]. ¹H NMR (300 MHz, DMSO-d₆) δ8.47-8.42 (m, 3H), 7.58-7.56 (m, 3H), 7.36 (d, J 8.7 Hz, 2H), 6.98 (d,J=8.4 Hz, 2H), 5.05 (s, 1H), 4.13 (s, 2H), 3.79 (s, 3H), 3.30-3.21 (m,4H), 1.69-1.49 (m, 4H) ppm. HPLC Column: Waters)(Bridge BEH C18 OBD PrepColumn, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 0.05% aqueousammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 10% B to22% B over 7 min. Detector: 220 and 254 nm.

Method C Example 13(R)-3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one(I-28)

Step 1.(R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

(R)-5-Allyl-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one(Intermediate 2-15, 100 mg, 0.23 mmol), chlorotris(triphenylphosphine)rhodium (I) (30 mg, 0.03 mmol), 1,4-diazabicyclo[2.2.2]octane (15 mg,0.14 mmol), (15 mg), and ethanol (50 mL) were added to a 100-mL 3-neckedround-bottom flask fitted with a nitrogen inlet, magnetic stir bar,condenser and thermometer. The resulting solution was stirred for 16 hat 90° C. Water (20 mL) was then added at room temperature and theresulting solution was extracted with ethyl acetate (5×20 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue was firstpurified by preparative TLC eluting with methanol/dichloromethane (1:10v/v) and then further purified by preparative HPLC to afford(R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one(I-28, 2.8 mg, 3%). LCMS: (ESI) m/z 395.17 [M+H]. ¹H NMR (300 MHz,CDCl₃) δ 9.75 (s, 1H), 7.72-7.92 (m, 1H), 7.26-7.41 (m, 4H), 7.12-7.23(m, 2H), 6.60 (s, 1H), 4.30-4.50 (m, 1H), 3.80-4.20 (m, 3H), 3.50-3.70(m, 1H), 3.10-3.50 (m, 2H), 2.80-3.10 (m, 1H), 2.30-2.78 (m, 2H),1.50-1.81 (m, 2H), 1.2-1.4 (m, 4H), 0.61-0.70 (m, 1H) ppm. HPLC Column:Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm. Mobilephase A: 0.05% aqueous ammonium bicarbonate/Mobile phase B:acetonitrile. Gradient: 55% B to 75% B over 7 min, then 100% B for 1min, then 55% for 1.5 min. Detector: 220 and 254 nm.

Method D Example 146-((1-Benzoyl-4-hydroxypiperidin-4-yl)methyl)-3-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(I-29)

Step 1.6-((1-Benzoyl-4-hydroxypiperidin-4-yl)methyl)-3-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

6-((4-Hydroxypiperidin-4-yl)methyl)-3-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-onetrifluoroacetic acid salt (Intermediate 2-21, 60 mg, 0.14 mmol), benzoicacid (21 mg, 0.17 mmol), HATU (80 mg, 0.21 mmol), DIPEA (55 mg, 0.43mmol), and dichloromethane (30 mL) were added to a 100-mL round-bottomflask fitted with a magnetic stir bar. The resulting solution wasstirred for 4 h at room temperature. The reaction mixture was thenquenched by the addition of water (20 mL) and extracted withdichloromethane (3×20 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by preparative HPLC to afford6-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-3-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(I-29), (13 mg, 22%). LCMS: (ESI) m/z 430.22 [M+H]. ¹H NMR (300 MHz,DMSO-d₆) δ 13.63 (br s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H),7.52-7.35 (m, 8H), 5.01 (s, 1H), 4.28-3.98 (m, 3H), 3.51-3.03 (m, 3H),1.70-1.32 (m, 4H). HPLC Column: Waters) (Bridge BEH Shield RP18 OBD PrepColumn, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 0.05% aqueousammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 15% B to52% B over 18 min. Detector: 220 and 254 nm.

Method E Example 156-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one(I-6)

Step 1.6-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar, athermometer and a condenser was charged with ethyl4-(ethoxymethyleneamino)-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate(Intermediate 2-22, 120 mg, 0.38 mmol),(4-(aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl)methanone(Intermediate 2-13, 95 mg, 0.38 mmol), and ethanol (30 mL). The solutionwas heated to reflux for 16 h in an oil bath and cooled to 23° C. Themixture was concentrated under reduced pressure and purified viapreparatory TLC eluting with methanol/dichloromethane (1:30 v/v). Themixture was further purified via preparatory HPLC to provide6-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one(I-6), (12.5 mg, 7%). ¹H NMR (300 MHz, DMSO-d₆) δ 1.33-1.74 (m, 4H),2.96-3.26 (m, 3H), 3.81 (s, 3H), 3.96-4.30 (m, 3H), 5.01 (brs, 1H),7.00-7.16 (m, 2H), 7.18-7.37 (m, 2H), 7.38-7.55 (m, 2H), 8.12 (s, 1H),8.22 (d, J=7.8 Hz, 2H), 14.28 (brs, 1H) ppm. LCMS (ESI) m/z 478 [M+H].HPLC Column: X Bridge Rp 18, 19×150 mm. Mobile phase A: 0.05% aqueousammonium carbonate/Mobile phase B: acetonitrile. Gradient: 10% B to 65%B over 10 min. Detector: 220 and 254 nm.

Method F Example 164-hydroxy-N,N-dimethyl-4-((7-oxo-3-(4-(2-(piperidin-1-yl)ethylamino)phenyl)isothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxamide(I-26)

Step 1. tert-butyl4-((3-(4-bromophenyl)-7-oxoisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate

A 250-mL round-bottom flask fitted with a magnetic stir bar, athermometer and a condenser was charged with3-(4-bromophenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate2-9, 1.5 g, 4.87 mmol), DMF (40 mL),6-tert-butyl-1,6[3]-dioxa-8-azaspiro[2.7]decan-7-one (1.25 g, 5.83mmol), and cesium carbonate (4.78 g, 14.67 mmol). The reaction mixturewas stirred for 16 h at 80° C. in an oil bath and then cooled to 23° C.The reaction was quenched with water (50 mL) and the product wasextracted with tert-butyl methyl ether (3×50 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography eluting with ethyl acetate/petroleum ether(2:1 v/v) to afford tert-butyl4-((3-(4-bromophenyl)-7-oxoisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate(1 g, 39%). LCMS (ESI) m/z 523 [M+H].

Step 2.3-(4-bromophenyl)-6-((4-hydroxypiperidin-4-yl)methyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwithtert-butyl4-((3-(4-bromophenyl)-7-oxoisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate(Step 1, 400 mg, 0.77 mmol), TFA (2 mL), and dichloromethane (30 mL).The resulting solution was stirred for 1 h at 23° C. The resultingmixture was then concentrated under reduced pressure to provide3-(4-bromophenyl)-6-((4-hydroxypiperidin-4-yl)methyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one,trifluoroacetic acid salt (420 mg, >95%) as a yellow solid used withoutfurther purification. LCMS (ESI) m/z 421 [M+H].

Step 3.4-((3-(4-bromophenyl)-7-oxoisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide

A 100-mL round-bottom flask fitted with a nitrogen inlet, a magneticstir bar and a thermometer was charged with3-(4-bromophenyl)-6-((4-hydroxypiperidin-4-yl)methyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one, trifluoroacetic acid salt (Step2, 400 mg, 3.72 mmol), dichloromethane (30 mL), and triethylamine (196mg, 1.92 mmol). A solution of N,N-dimethylcarbamoyl chloride (140 mg,0.28 mmol) in dichloromethane (10 mL) was then added dropwise at 0° C.and the resulting mixture was stirred for 1 h. The reaction was thenquenched with water (20 mL) and washed with ethyl acetate (5×20 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with dichloromethane/methanol(20:1 v/v) to give4-((3-(4-bromophenyl)-7-oxoisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)-4-hydroxy-N,N-dimethyl-piperidine-1-carboxamide(200 mg, 48%) and used in the next step without further purification.LCMS: (ESI) m/z 492 [M+H].

Step 4.4-hydroxy-N,N-dimethyl-4-((7-oxo-3-(4-(2-(piperidin-1-yl)ethylamino)phenyl)isothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxamide

A 5-mL microwave tube fitted with a magnetic stir bar was charged with4-((3-(4-bromophenyl)-7-oxoisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)-4-hydroxy-N,N-dimethyl-piperidine-1-carboxamide(Step 3, 200 mg, 0.40 mmol), dioxane (3 mL),2-(piperidin-1-yl)ethan-1-amine (75 mg, 0.60 mmol),bis(dibenzylideneacetone)palladium (50 mg, 0.04 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (25 mg, 0.05mmol), and cesium carbonate (265 mg, 0.90 mmol). The reaction mixturewas irradiated with a microwave for 1 h at 120° C. After the mixture wascooled to 23° C., the reaction was quenched with water (20 mL). Theproduct was extracted with ethyl acetate (5×20 mL). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was further purified by preparative HPLCto afford4-hydroxy-N,N-dimethyl-4-((7-oxo-3-(4-(2-(piperidin-1-yl)ethylamino)phenyl)isothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxamide(I-26), (10.5 mg, 5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.33-1.42 (m, 4H), 1.48-1.64 (m, 6H), 2.35-2.46 (m, 6H), 2.72 (s, 6H),2.94-3.01 (m, 2H), 3.17-3.22 (m, 2H), 3.27-3.34 (m, 2H), 4.08 (s, 2H),4.91 (brs, 1H), 6.02 (t, J=5.4 Hz, 2H), 6.70 (d, J=8.8 Hz, 2H), 8.27 (d,J=8.8 Hz, 1H), 8.42 (s, 1H) ppm. LCMS (ESI) m/z 540 [M+H]. HPLC Column:XBridge Prep C18, 5 μm OBD, 19×150 mm. Mobile phase A: 0.05% aqueousammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 10% B to50% B over 15 min. Flow rate: 20 mL/min. Detector: 220 and 254 nm.

Method G Example 176-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-(2-(2-oxoimidazolidin-1-yl)ethoxy)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one(I-27)

Step 1. tert-butyl4-hydroxy-4-((3-(3-methoxyphenyl)-7-oxoisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxylate

3-(3-methoxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate2-10, 800 mg, 3.09 mmol), DMF (25 mL), tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate (788 mg, 3.69 mmol), andcesium carbonate (3 g, 9.21 mmol) were added to a 250-mL round-bottomflask fitted with a magnetic stir bar and a condenser. The resultingsolution was stirred for 14 h at 90° C. in an oil bath. The reaction wasthen quenched by the addition of water (100 mL). The solids werecollected by filtration and the resulting mixture was concentrated underreduced pressure to afford3-(3-methoxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (850 mg, 60%)used in next step without further purification. LCMS (ES) m/z 473 [M+H].

Step 2.6-((4-hydroxy-1-(2,2,2-trifluoroacetyl)-1l4-piperidin-4-yl)methyl)-3-(3-methoxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

tert-butyl4-hydroxy-4-((3-(3-methoxyphenyl)-7-oxoisothiazolo[4,5-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxylate(Step 1, 850 mg, 1.80 mmol), dichloromethane (20 mL), andtrifluoroacetic acid (3 mL) were added to a 100-mL round-bottom flaskfitted with a magnetic stir bar. The resulting solution was stirred for3 h at 23° C. The mixture was concentrated under reduced pressure toafford6-((4-hydroxy-1-(2,2,2-trifluoroacetyl)-1l4-piperidin-4-yl)methyl)-3-(3-methoxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one,trifluoroacetic acid salt (800 mg, 76%) used in next step withoutfurther purification. LCMS (ES) m/z 373 [M+H].

Step 3.6-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-methoxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

6-((4-hydroxy-1-(2,2,2-trifluoroacetyl)-1l4-piperidin-4-yl)methyl)-3-(3-methoxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one,trifluoroacetic acid salt (Step 2, 800 mg, 1.64 mmol), DMF (30 mL),cyclopropanecarboxylic acid (180 mg, 2.09 mmol), HATU (950 mg, 2.50mmol), and DIPEA (700 mg, 5.42 mmol) were added to a 250-mL round-bottomflask fitted with a magnetic stir bar. The resulting solution wasstirred for 1 h at 23° C. The reaction was quenched by the addition ofwater (150 mL). The solids were removed by filtration and the resultingmixture was concentrated under reduced pressure to afford6-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-methoxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one(790 mg) used in the next step without further purification. LCMS (ES)m/z) 441 [M+H].

Step 4.6-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-hydroxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

To a 250-mL 3-necked round-bottom flask purged and maintained under aninert atmosphere of nitrogen and with a magnetic stir bar was added6-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-methoxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one(Step 3, 790 mg, 1.79 mmol) and dichloromethane (40 mL). A solution ofboron tribromide (4 g, 16 mmol) in dichloromethane (16 mL) was thenadded at 0° C. The resulting solution was warmed to 23° C. and stirredfor 16 h. The reaction was then quenched with water (40 mL). The solidswere removed by filtration, and the solvents were removed under reducedpressure to afford6-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-hydroxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one (500 mg, 66%) used without furtherpurification. LCMS (ESI) m/z 427 [M+H].

Step 5.6-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-(2-(2-oxoimidazolidin-1-yl)ethoxy)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one

To a 100-mL round-bottom flask purged and maintained under an inertatmosphere of nitrogen and with a magnetic stir bar was added6-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-hydroxyphenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one(Step 4, 150 mg, 0.35 mmol), tetrahydrofuran (25 mL),1-(2-hydroxyethyl)imidazolidin-2-one (183 mg, 1.41 mmol, 4.00 equiv),and triphenylphosphine (369 mg, 1.41 mmol) followed by the slow additionof DEAD (246 mg, 1.41 mmol, 4.02 equiv) in tetrahydrofuran (1 mL) withstirring at 0° C. over 15 min. The reaction was stirred for 16 h at 23°C. and then quenched with methanol (20 mL). The solution was thenconcentrated under reduced pressure and purified via silica gel columnchromatography eluting with dichloromethane/methanol (20:1). Thecollected fractions were combined and concentrated under reducedpressure. The residue was further purified by preparatory HPLC to afford6-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-(3-(2-(2-oxoimidazolidin-1-yl)ethoxy)phenyl)isothiazolo[4,5-d]pyrimidin-7(6H)-one(I-27), (8.6 mg, 5%). LCMS (ESI) m/z 539 [M+H]. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.49 (s, 1H), 8.06-8.02 (m, 2H), 7.51-7.47 (m, 1H), 7.16-7.13(m, 1H), 6.39 (s, 1H), 5.04 (s, 1H), 4.17-4.00 (m, 6H), 3.50-3.45 (m,4H), 3.40-3.33 (m, 1H), 3.25-3.22 (m, 2H), 2.98-2.96 (m, 1H), 1.99-1.96(m, 1H), 1.62-1.48 (m, 4H), 0.78-0.69 (m, 4H) ppm. HPLC Column: XBridgePrep C18 OBD Column, 5 pin, 19×150 mm. Mobile phase A: 10 mmol aqueousammonium bicarbonate/Mobile Phase B: acetonitrile. Gradient: 28% B over14 min. Detector: 220 and 254 nm.

Biochemical Assays Example 18 USP7 Assay A (Ubitquin-Rhodamine 110Assay)

Each assay was performed in a final volume of 15 μl in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 1 mM GSH (L-Glutathione reduced; Sigma #G4251),0.03% BGG (0.22 μM filtered, Sigma, #G7516-25G), and 0.01% Triton X-100(Sigma, #T9284-10L). Nanoliter quantities of either an 8-point or10-point, 3-fold serial dilution in DMSO was pre-dispensed into assayplates (Perkin Elmer, ProxiPlate-384 F Plus, #6008269) for a final testconcentration range of either 25 μM to 11 nM or 25 μM to 1.3 nM,respectively. The final concentration of the enzyme (USP7, constructUSP7 (208-1102) 6*His, Viva Biotech) in the assay was 62.5 pM. Finalsubstrate (Ub-Rh110; Ubiquitin-Rhodamine 110, R&D Systems #U-555)concentration was 25 nM with [Ub-Rh110]<<Km. 5 μL of 2× enzyme was addedto the assay plates (pre-stamped with compound) and preincubated withUSP7 for 30 min. 5 μL of 2×Ub-Rh110 was then added to assay plates.Plates were incubated stacked for 20 min at room temperature before 5 μlof stop solution (final concentration of 10 mM citric acid in assaybuffer (Sigma, #251275-500G)). Fluorescence was read on the Envision(Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on thePheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).

Example 19 USP7 Assay B (Ubitquin-Rhodamine 110 Assay)

Each assay was performed in a final volume of 20 μl in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 2 mM CaCl₂ (1M calcium chloride solution; Sigma#21114), 1 mM GSH (L-Glutathione reduced; Sigma #G4251), 0.01% Prionex(0.22 μM filtered, Sigma #G-0411), and 0.01% Triton X-100. Stockcompound solutions were stored at −20° C. as 10 mM in DMSO. Up to 1month prior to the assay, 2 mM test compounds were pre-dispensed intoassay plates (Black, low volume; Corning #3820) and frozen at −20° C.Prestamped assay plates were allowed to warm to room temperature on theday of the assay. For the screen, 100 nL of 2 mM was pre-dispensed for afinal screening concentration of 10 μM (DMSO_((fc))=0.5%). For follow-upstudies, 250 nL of an 8-point, 3-fold serial dilution in DMSO waspre-dispensed into assay plates for a final test concentration of 25 μM11 nM (1.25c % DMSO final concentration). Unless otherwise indicated,all follow-up assays were run on triplecate plates. Enzyme (USP7,construct Met (208-1102)-TEV-6*His; Viva Q93009-1) concentration andincubation times were optimized for the maximal signal-to-backgroundwhile maintaining initial velocity conditions at a fixed substrateconcentration. The final concentration of the enzyme in the assay waseither 75 pM or 250 pM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine110, R&D Systems (biotechne)#U-555) concentration was 25 nM with[Ub-Rh110]<<Km. Compounds were either not preincubated or preincubatedwith USP7 between 30 to 120 min prior to the addition of 10 μL of2×Ub-Rh110 to compound plates. Plates were incubated stacked for either23 or 45 min at room temperature before fluorescence was read on theEnvision (Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) oron the PheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMGLabtech).

Data from USP7 Assays A and B were reported as percent inhibition (inh)compared with control wells based on the following equation: %inh=1−((FLU−Ave_(Low))/(Ave_(High)−Ave_(Low))) where FLU=measuredFluorescence, Ave_(Low)=average Fluorescence of no enzyme control(n=16), and Ave_(High)=average Fluorescence of DMSO control (n=16). IC₅₀values were determined by curve fitting of the standard 4 parameterlogistic fitting algorithm included in the Activity Base softwarepackage: IDBS XE Designer Model 205. Data was fitted using the LevenburgMarquardt algorithm. IC₅₀ data from USP7 Assays A-B for the compounds ofthe disclosure are shown below in Table 7.

TABLE 7 USP7 activity of compounds of the disclosure in USP7 assay A andB. Com- LCMS: HPLC pound Intermediate (ESI) m/z retention No.: Method InSynthesis [M + 1] time/min USP7_IC50 I-1 A 2-7 465.19 1.71 + I-2 B 2-2,2-5 495.28 1.46 ++ I-3 B 2-4, 2-1 495.28 1.49 ++ I-4 B 2-11, 2-2 495.251.15 ++ I-5 B 2-2, 2-19 466 2.87 +++ I-6 E 2-22, 2-13 478 1.17 ++++ I-7E 2-23, 2-14 460 1.05 ++ I-8 B 2-7, 2-1 477.27 1.43 ++ I-9 B 2-2, 2-6525 3.03 + I-10 A 2-16, 2-4 564 0.839 + I-11 A 2-7 489.2 1.66 +++ I-12 A2-7 489.2 15 ++++ I-13 A 2-7 489.2 21.2 ++ I-14 A 2-7 479.2 1.38 ++ I-15A 2-7 479.2 4.41 ++ I-16 A 2-7 479.2 5.77 ++ I-17 A 2-7, 2-17 525 3.05++ I-18 A 2-7, 2-17 525 14.41 + I-19 A 2-7, 2-17 525 11.59 +++ I-20 A2-19 478 2.82 ++ I-21 A 2-20 490 2.46 +++ I-22 F 2-8 516 1.01 ++ I-23 B2-12, 2-2 495 1.2 ++ I-24 B 2-12, 2-1 507 1.16 ++ I-25 A 2-4 485 1.56 +I-26 F 2-9 540 1.38 ++ I-27 G, A 2-10 539 1.07 ++ I-28 C 2-15 395.170.91 ++++ I-29 D 2-21 430.22 1.39 +++ I-30 B 2-2, 2-4 483.25 1.52 + I-31B 2-5, 2-1 507.34 1.43 ++ ++++ indicates an IC₅₀ of less than about 0.5μM, +++ indicates an IC₅₀ between about 0.5 μM and about 1 μM, ++indicates an IC₅₀ between about 1 μM and about 10 μM, and + indicates anIC₅₀ greater than 10 μM.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

The invention claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof, wherein: X₁ is C, S, or S(O); X₂ is S or NR₆; X₃ is N or CR₇, wherein, one of X₂ or X₃ is N; R₁ is H, OH, SH, NH₂, or F; R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₈; R₃ is independently at each occurrence selected from D, (C₁-C₆) alkyl R₄ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₂; R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, or CN; R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆) haloalkyl; R₇ is H, D, (C₁-C₆) alkyl, halogen, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₄; each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl, —CN, —C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀, —NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀, —NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyl optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form an aryl ring optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R₉; each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, —OH, CN, —C(O)R₂₁, —C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂, —NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₂₄; R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₆; or R₁₀ and R₁₁ together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R₁₆; each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆, —NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆, halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyl optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form an aryl ring optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R₁₃; each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₂₇; each R₁₄ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, —OH, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₅; each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, OH, or CN; each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₇; each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, or CN; each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₂₃; each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₂₃; each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN; each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆, —NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅, —S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH, or CN; each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl; each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; m is 0 or 1; n is 1; and q is independently at each occurrence 0, 1, or
 2. 2. The compound of claim 1, wherein X₁ is C.
 3. The compound of claim 1, wherein X₂ is S and X₃ is N.
 4. The compound of claim 1, wherein X₂ is NR₆ and X₃ is CR₇.
 5. The compound of claim 1, wherein R₁ is OH.
 6. The compound of claim 1, wherein R₄ is H (C₆-C₁₄) aryl, or heteroaryl.
 7. The compound of claim 1, wherein R₅ is H.
 8. The compound of claim 1, wherein R_(5′) is H.
 9. The compound of claim 1, wherein is R₆ is H.
 10. The compound of claim 1, wherein R₇ is H.
 11. The compound of claim 1, having Formula (Ia), Formula (Id) or Formula (Ig):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or thereof, wherein: X₁ is C, S, or S(O); R₁ is H, OH, SH, NH₂, or F; R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₈; R₃ is independently at each occurrence selected from D, (C₁-C₆) alkyl R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₂; R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, or CN; each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl, —CN, —C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀, —NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀, —NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyl optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form an aryl ring optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R₉; each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, OH, CN, —C(O)R₂₁, —C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂, —NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₂₄; R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₆; or R₁₀ and R₁₁ together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R₁₆; each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆, —NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆, halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyl optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form an aryl ring optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R₁₃; each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₂₇; each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₇; each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, or CN; each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₂₃; each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₂₃; each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN; each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆, —NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅, —S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH, or CN; each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl; each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; m is 0 or 1; n is 1; and q is independently at each occurrence 0, 1, or
 2. 12. The compound of claim 1, having Formula (Ib), Formula (Ie), or Formula (Ih):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X₁ is C, S, or S(O); R₁ is H, OH, SH, NH₂, or F; R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₈; R₃ is independently at each occurrence selected from D, (C₁-C₆) alkyl R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₂; R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, or CN; R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆) haloalkyl; each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl, —CN, —C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀, —NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀, —NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyl optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form an aryl ring optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R₉; each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, OH, CN, —C(O)R₂₁, —C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂, —NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₂₄; R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₆; or R₁₀ and R₁₁ together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R₁₆; each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆, —NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆, halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyl optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form an aryl ring optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R₁₃; each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₂₇; each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₇; each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, or CN; each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₂₃; each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₂₃; each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN; each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆, —NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅, —S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH, or CN; each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl; each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; m is 0 or 1; n is 1; and q is independently at each occurrence 0, 1, or
 2. 13. The compound of claim 1, having Formula (Ic), Formula (If), or Formula (Ii):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof, wherein: X₁ is C, S, or S(O); R₁ is H, OH, SH, NH₂, or F; R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₈; R₃ is independently at each occurrence selected from D, (C₁-C₆) alkyl R₄ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₂; R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, or CN; R₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆) haloalkyl; R₇ is H, D, (C₁-C₆) alkyl, halogen, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₁₄; each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl, —CN, —C(O)R₁₉, —CO(O)R₁₉, —C(O)NR₁₉R₂₀, —S(O)_(q)R₁₉, —S(O)_(q)NR₁₉R₂₀, —NR₁₉S(O)_(q)R₂₀, —(C₀-C₃)-alkylene-NR₁₉R₂₀, —NR₁₉C(O)R₂₀, —NR₁₉C(O)C(O)R₂₀, —NR₁₉C(O)NR₁₉R₂₀, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₉, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyl optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form an aryl ring optionally substituted with one or more R₉; or two R₈ together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R₉; each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl, —NH₂, OH, CN, —C(O)R₂₁, —C(O)NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂, —NR₂₁S(O)_(q)R₂₂, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₂₄; R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₆; or R₁₀ and R₁₁ together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R₁₆; each R₁₂ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₅R₂₆, —S(O)_(q)NR₂₅R₂₆, —NR₂₅R₂₆, —NR₂₅C(O)NR₂₅R₂₆, —NR₂₅C(O)OR₂₆, —NR₂₅S(O)_(q)R₂₆, —NR₂₅C(O)R₂₆, halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form a (C₃-C₈) cycloalkyl optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form an aryl ring optionally substituted with one or more R₁₃; or two R₁₂ together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R₁₃; each R₁₃ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₂₇; each R₁₄ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, —OH, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₅; each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, OH, or CN; each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R₁₇; each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; each R₁₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, or CN; each R₁₉ and R₂₀ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₂₃; each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R₂₃; each R₂₃ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN; each R₂₄ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₅C(O)R₂₆, —NR₂₅S(O)_(q)R₂₆, —C(O)R₂₅, —C(O)NR₂₅R₂₆, —NR₂₅R₂₆, —S(O)_(q)R₂₅, —S(O)_(q)NR₂₅R₂₆, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH, or CN; each R₂₅ and R₂₆ is independently at each occurrence H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl; each R₂₇ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; m is 0 or 1; n is 1; and q is independently at each occurrence 0, 1, or
 2. 14. The compound of claim 1 selected from: 6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-methoxyphenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-[3-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-fluorophenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one; 6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-methoxyphenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one; 6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-phenyl-1H, 6H,7H-pyrazolo[4,3-d]pyrimidin-7-one; 6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 3-(4-fluoro-3-methoxyphenyl)-6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 3-(4-fluorophenyl)-6-({4-hydroxy-1-[5-(4-methylpiperazin-1-yl)pyridine-2-carbonyl]piperidin-4-yl}methyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-{[4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-({4-hydroxy-1-[(3S)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-{[1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-({1-[(3R)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-({1-[(3S)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-1H, 6H,7H-pyrazolo[4,3-d]pyrimidin-7-one; 6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-(4-methoxyphenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one; 4-({3-[4-fluoro-3-(piperazin-1-yl)phenyl]-7-oxo-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-6-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide; 6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-[4-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-[4-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; 4-hydroxy-N,N-dimethyl-4-{[7-oxo-3-(4-{[2-(piperidin-1-yl)ethyl]amino}phenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]methyl}piperidine-1-carboxamide; 1-[2-(3-{6-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-7-oxo-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-3-yl}phenoxy)ethyl]imidazolidin-2-one; 3-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one; 6-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-3-phenyl-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one; 6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-fluorophenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; or 6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-(4-methoxyphenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one.
 15. A pharmaceutical composition comprising, a compound of claim 1, and a pharmaceutically acceptable carrier. 